Charcot-Marie-Tooth Disease

By Eleanor R Hethcox ACNP-BC

Charcot-Marie-Tooth Disease

bull One of the most common inherited neurological disorders

bull Prevalence is 17-40100000 world wide

bull Affecting approximately 1 in 2500 people in the US

bull Affects male and females and all cultures

bull First identified in 1886 by Martin Charcot Pierre Marie and

Howard Henry Tooth

bull AKA ndash Hereditary Motor and Sensory Neuropathy (HMSN)

or peroneal muscular atrophy

bull Affects peripheral nerves ndash specifically related to the

myelin sheath and axons

Charcot-Marie-Tooth Disease

bull Many forms of CMT exist (CMT1234X)

bull Normal life expectancy CMT is not fatal

bull Onset of symptoms is most often in adolescence or early

adulthood

bull Progression of symptoms is very gradual

bull Slow progressing weakness beginning in the distal limb

muscles generally is noted Usually starts in lower

extremities before it starts in the upper extremities

bull Severity of symptoms may vary greatly among affected

individuals

Types of Hereditary Neuropathies

Charcot-Marie-Tooth Disease

bull A clinically and genetically heterogenous group of

disorders caused by mutations in genes that affect the

normal function of the peripheral nerves

Image from Muscular Dystrophy Association of NSW

httpwwwmdnsworgauoldFactsSheetsCMThtm

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot-Marie-Tooth Disease

bull One of the most common inherited neurological disorders

bull Prevalence is 17-40100000 world wide

bull Affecting approximately 1 in 2500 people in the US

bull Affects male and females and all cultures

bull First identified in 1886 by Martin Charcot Pierre Marie and

Howard Henry Tooth

bull AKA ndash Hereditary Motor and Sensory Neuropathy (HMSN)

or peroneal muscular atrophy

bull Affects peripheral nerves ndash specifically related to the

myelin sheath and axons

Charcot-Marie-Tooth Disease

bull Many forms of CMT exist (CMT1234X)

bull Normal life expectancy CMT is not fatal

bull Onset of symptoms is most often in adolescence or early

adulthood

bull Progression of symptoms is very gradual

bull Slow progressing weakness beginning in the distal limb

muscles generally is noted Usually starts in lower

extremities before it starts in the upper extremities

bull Severity of symptoms may vary greatly among affected

individuals

Types of Hereditary Neuropathies

Charcot-Marie-Tooth Disease

bull A clinically and genetically heterogenous group of

disorders caused by mutations in genes that affect the

normal function of the peripheral nerves

Image from Muscular Dystrophy Association of NSW

httpwwwmdnsworgauoldFactsSheetsCMThtm

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot-Marie-Tooth Disease

bull Many forms of CMT exist (CMT1234X)

bull Normal life expectancy CMT is not fatal

bull Onset of symptoms is most often in adolescence or early

adulthood

bull Progression of symptoms is very gradual

bull Slow progressing weakness beginning in the distal limb

muscles generally is noted Usually starts in lower

extremities before it starts in the upper extremities

bull Severity of symptoms may vary greatly among affected

individuals

Types of Hereditary Neuropathies

Charcot-Marie-Tooth Disease

bull A clinically and genetically heterogenous group of

disorders caused by mutations in genes that affect the

normal function of the peripheral nerves

Image from Muscular Dystrophy Association of NSW

httpwwwmdnsworgauoldFactsSheetsCMThtm

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Types of Hereditary Neuropathies

Charcot-Marie-Tooth Disease

bull A clinically and genetically heterogenous group of

disorders caused by mutations in genes that affect the

normal function of the peripheral nerves

Image from Muscular Dystrophy Association of NSW

httpwwwmdnsworgauoldFactsSheetsCMThtm

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot-Marie-Tooth Disease

bull A clinically and genetically heterogenous group of

disorders caused by mutations in genes that affect the

normal function of the peripheral nerves

Image from Muscular Dystrophy Association of NSW

httpwwwmdnsworgauoldFactsSheetsCMThtm

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Normal function of axon and myelin sheath

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Classification of CMT

bull Myelin vs Axon

bull Demyelinating

HMSNCMT type 1

bull Intermediate

bull Axonal HMSNCMT

type 2

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Peripheral Neuropathy

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT ndash Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Inheritance Patterns

bull Extensive underling genetic heterogeneity

bull The CMT spectrum of disorders can be inherited in the following ways

1) Autosomal dominant

2) Autosomal recessive

3) X-linked inheritance (dominant and recessive)

(Spontaneous mutations have been reported)

bull More than 40 genes have been implicated as causes of

the various forms of CMT

bull Most commonly identified subtypes CMT1A CMTX1 hereditary

neuropathy with liability to pressure palsies CMT1B and CMT2A

Together these 5 subtypes account for 92 of genetically defined CMT

cases All other CMT subtypes amp assoc mutations each accounted for

lt1 of genetically defined CMT

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Other Influences on CMT Phenotype

Even among family members with the same type of CMT

symptoms can vary widely It is therefore possible that other

genetic or environmental factors affect the development of

CMT

Comorbidities Nutritional Environment

Diabetes Mellitus

Obesity

Hypothyroidism

Exposure to Toxins

Genetic Background

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot Marie Tooth Types

CMT Type Chromosome

Inheritance

Pattern

Age of Onset Clinical Features Average

NCVs

CMT 1A

(PMP-22 dupl)

17p11AD First decade Distal Weakness 15-20 ms

CMT 1B (P0-

MPZ)

1q22AD First decade Distal Weakness lt20ms

CMT 1C CMT

(nonA nonB)

16p13AD Second

decade

Distal Weakness 26-42 ms

CMT 1D (early

growth

response

[EGR]-2)

10q21 AD First decade Distal Weakness 15-20 ms

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT ndash Types Continued

CMT

Type

Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21 AD 1st decade Distal weakness 15-20 ms

CMT 1E 17p11 AD 1st decade Distal weakness 15-20 ms

CMT 1F 8p21 AD 1st decade Distal weakness 15-20 ms

CMT X Xq13 XD 2nd decade Distal weakness 25-40 ms

CMT 2A 1p36 AD 10 y Distal weakness gt 38 ms

CMT 2B 3q AD 2nd decade Distal weakness sensory loss

skin ulcers

Axon loss

normal

CMT 2C 12q23-q24 AD 1st decade Vocal cord diaphragm amp distal

weaknessgt 50 ms

CMT 2D 7p14 AD 16-30y Distal weakness upper limb

predominantly

Axon loss

normal

CMT 2E 8p21AD 10-30y Distal weakness lower limb

predominantly

Axon

lossnormal

CMT 2F 7q11-21 AD 15-25y Distal weakness Axon loss

normal

CMT 2G 12q12-q13 AD 9-76y Distal weakness Axon loss

normal

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Types Continued

CMT

Type

Chromosome

Inheritance Pattern

Age of

Onset

Clinical Features Average NCV

CMT 2H AR 15-25y Distal weakness

pyramidal features

Axon loss

Normal

CMT 2I 1q22 AD 47-60y Distal weakness Axon loss

Normal

CMT 2J 1q22 AD 40-50y Distal weakness

hearing loss

Axon

lossnormal

CMT 2K 8q13-q21 AR lt 4y Distal weakness Axon loss

normal

CMT 2L 12q24 AD 15-25y Distal weakness Axon loss

normal

CMT R-

Ax (moroccan)

1q21- AR 2nd

decade

Distal weakness Axon loss

normal

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Types Continued

Type Chromosome

Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

Cowchock

syndrome

Xq24-q26 1st

decade

Distal weakness

deafness mental

retardation

Axon loss

normal

HNPP (PMP-

22) or

tomaculous

neuropathy

17p11 AD All ages Episodic weakness and

numbness

Conduction

blocks

Dejerine-

Sottas

syndrome

(DSS) or

HMSN 3

P0 AR

PMP- 22 AD

8q23 AD

2y Severe weakness lt 10 ms

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT types Continued

CMT type Chromosomeinheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0 EGR2 or PMP-22

AR

Birth Severe weakness lt 10 ms

CMT 4A 8q13 AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein ndash 2)

11q23 AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23 AR 5-15y Delayed walking 14-32 ms

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24 AR 1-10y Distal muscle wasting

foot and hand

deformities

10-20 ms

CMT 4E (EGR2) 10q21 AR Birth Infant hypotonia 9-20 ms

CMT 4G 10q23 AR 8-16y Distal weakness 9-20 ms

CMT 4H 12p1121-q1311AR 0-2y Delayed walking 9-20 ms

CMT 4F 19q13AR 1-3y Motor delay absent

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT ndash Types (AD X-linked AR)

bull CMT 2D

bull CMT 2E

bull CMT 2F

bull CMT 2G

bull CMT 2H

bull CMT 2I

bull CMT 2J

bull CMT 2K

bull CMT 2L

bull CMT R-Ax

(Ouvrier)

bull CMT 1A

bull CMT 1B

bull CMT 1C

bull CMT 1D

bull CMT 1E

bull CMT 1F

bull CMT X

bull CMT 2A

bull CMT 2B

bull CMT 2C

bull CMT R-Ax

(Moroccan)

bull Cowchock

syndrome

bull HNPP (tomaculous

neuropathy)

bull DSS

bull Congenital

hypomyelination

(CH)

bull CMT 4A

bull CMT 4B

bull CMT 4C

bull CMT 4D

bull CMT 4E

bull CMT 4G

bull CMT 4H

bull CMT 4F

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Most common CMT CMT linked types

bull CMT1A

bull CMT1B

bull CMT X1

bull CMT2A

bull HNPP (linked to CMT but not a type of

CMT)

These types occur most

commonly

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Type 1 A

PMP22

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Genetics of CMT1 ndash demyelinating

bull Caused by

mutations in genes

that are expressed

in Schwann cells

bull Exhibit AD AR and

X-linked inheritance

bull Subdivided in types

ABCetc

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Type 1A Pedigree

bull Autosomal Dominant Inheritance

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT 1A ndash Autosomal Dominant Form

bull Most common type of CMT

bull PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

bull Largely unknown but

thought to have a role in

the initiation of myelin

spirals regulation of

growth amp differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT1A ndash PMP22 gene

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT 1A

bull Duplication of PMP-22

bull Chromosome affected

ndash 17p11

bull Autosomal Dominant

bull Age of Onset ndash first

decade of life

bull Clinical features ndash

distal weakness

bull Average NCV is 15-20

ms

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Type 1B

Gene ndash Myelin Protein Zero

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot Marie Tooth 1B

bull MPZ or Myelin Protein Zero

bull Normal function of MPZ is that of an adhesion molecule

bull Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot Marie Tooth 1B (CMT 1B)

bull Autosomal Dominant

bull Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0)

bull Chromosome 1q22

bull Age of onset ndash first decade

bull Distal weakness

bull Avg NCV lt 20 ms

bull Less common than CMT1A

bull Mutations in the MPZ gene account for less than 5 of

CMT1 cases

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT X1

Other Subtypes 23Cowchock syndrome 5

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT X1

bull X-linked Dominant inheritance

bull Age of Onset is in the second decade of life

bull Clinical features include distal weakness

bull Average NCV ndash 25-40 ms

bull Caused by mutations in the gap junction protein beta 1 (GJB1 gene)

aka connexin 32 gene on chromosome Xq13

bull GJB1 encodes a gap junction protein that plays an important role in the

homeostasis of myelinated axons

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT X1

bull Gene is expressed in myelinating Schwann cells but not

incorporated into the myelin sheath

bull Both sexes are affected symptoms more prominent in

boys

bull Gait problems foot deformities (pes planus or pes cavus)

bull Less common features include tremor hand weakness and

sensorineural deafness

bull Demyelination and axonal loss is observed histologically

but onion bulb formation is minimal

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Hereditary neuropathy

with liability to pressure palsies

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

HNPP

bull Peripheral nerve disorder

bull Linked to CMT

bull PMP22 deletion or point

mutation responsible for

HNPP

bull Age of onset ndash all ages

bull Clinical features ndash episodic

weakness amp numbness

bull Conduction blocks

bull Autosomal dominant

Defects of PMP22

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot Marie Tooth

Type CMT2A

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT2A

bull Most common CMT2 Phenotype

ndash Axonal degeneration

bull Maps to chromosome 1p35-36

bull Gene most commonly

implicated is mitochondrial

fusion protein mitofusin 2

(MFN2)

bull Other genes implicated include

MT-ATP6 Dynamin 2

bull Majority of these cases are

autosomal dominant but the

genetic basis of CMT2 is

heterogenous like CMT1

bull Many other subtypes of CMT2

exist including BCDE etc

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT2 pedigree ndash nonsense mutation in

DHTKD1

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot Marie Tooth

Work-up

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Diagnosis of CMT Disease

bull Complete Medical

History and Physical

Examination

bull Family History very

important

bull Neurological

Examination

bull Genetic Testing

bull Nerve Conduction

Studies

bull Electromyography

bull Nerve biopsy

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Signs amp Symptoms

bull CMT affects both sensory

and motor nerves

bull Onset of symptoms most

often in adolescence or

early adulthood

bull Onset can also occur in

mid-adulthood

bull Progression of symptoms

is gradual

bull Normal life expectancy

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

CMT Signs amp Symptoms

bull Weakness of foot and

lower leg muscles

bull Foot drop

bull High Stepped Gait

wfrequent tripping or

falls

bull ldquoinverted champagne

bottlerdquo appearance of

lower legs

bull High arches

bull Hammer toes

bull Pes Cavus deformity

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Findings of CMT

bull Historyndash Significant family history

ndash Slowly progressing weakness

beginning in the distal limb muscles

ndash Muscle wasting weakness

ndash Onset usually occurs in the first 2

decades of life

ndash Initial co difficulty walking frequent

tripping due to foot and distal leg

weakness Frequent ankle sprains

and falls

ndash Child can be clumsy andor not

athletic

ndash Foot drop commonly occurs

ndash Steppage is common (gait)

ndash Foot deformity (pes cavus)

bull Physicalndash Distal wasting in legs ndash ldquostork leg or

inverted champagne bottle

appearancerdquo

ndash Pes cavus (high arch foot)

ndash Spinal deformities (thoracic

scoliosis) in 37-50 of patients with

CMT type 1

ndash DTRs are markedly diminished or

absent

ndash Vibration sensation and

proprioception are significantly

decreased

ndash Sensory gait ataxia and positive

Romberg test

ndash Sense of paintemp is intact

ndash Essential tremor in 30-50 of

patients

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Genetic Testing for Charcot Marie Tooth

bull For family planning purposes

bull Natural history studies

bull Entry into clinical trials

bull Usually very expensive

bull Can be confusing for patients

bull Most general practitioners also confused due to locus

heterogeneity

bull Has implications for medical treatments

bull Several algorithms have been developed

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Genetic Testing Algorithms

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Algorithm for Genetic Testing CMT

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Algorithm for Genetic Testing CMT

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Algorithm for Genetics Testing CMT

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Management of CMT

bull Is supportive only

bull Disease-modifying therapy IS NOT available

bull Physical Therapy

bull Occupational Therapy

bull Braces and other orthopedic devices

bull Orthopedic surgery

bull Analgesics for severe pain

bull Muscle strengthening to delay or reduce muscle atrophy

bull Avoidance of drugs known to exacerbate CMT symptoms

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Charcot Marie Tooth

Latest Therapies

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Promising Research for New CMT Treatments

bull Lck tyrosine kinase mediates β1-integrin signaling to

regulate Schwann cell migration and myelination

bull What we have found is that Lck is essentially the switch

that signals migration of the Schwann cells and production

of the myelin sheath Dr Tapinos said This finding sets

the stage for further research into the specific molecular

mechanisms that occur in order for this process to break

down and eventually toward developing treatments to

prevent it

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Promising Research for New CMT Therapies

bull April 2013

bull Hitting lsquoresetrsquo in protein synthesis restores myelination suggests new

treatment for misfolded protein diseases such as CMT Alzheimerrsquos

bull Lawrence Wrabetz MD director of the institute and professor of neurology and

biochemistry in UBrsquos School of Medicine and Biomedical Sciences ldquoThe

misfolded protein diseases are an interesting and challenging group of

diseases to study CMT for example is caused by mutations in more than 40

different genesrdquo he says ldquoWhen there are so many different genes

involved and so many different mechanisms you have to find a unifying

mechanism this problem of Gadd34 turning protein synthesis on at too high a

level could be one unifying mechanism The hope is that this proof of principle

applies to more than just CMT and may lead to improved treatments for

Alzheimerrsquos Parkinsonrsquos Type 1 diabetes and the other diseases caused by

misfolded proteinsrdquo

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Integrative Therapies for CMT

bull L-carnitine

bull TENS

bull Aconite ndash homeopathic

bull Biotin

bull Folate

(NOTE There is lack of sufficient scientific data on use of

these therapies for treatment of CMT)

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Latest Research and Clinical Trials

bull Natural History Evaluation of Charcot Marie Tooth Disease (CMT)

Types CMT1B CMT2A CMT4A CMT4C and Others

bull Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

bull Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A New

Causes of CMT2

bull Treadmill Stretching and Proprioceptive Exercise (TreSPE)

Rehabilitation Program for CharcotminusMarieminusTooth Neuropathy Type 1A

(CMT1A)

bull Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale

for Children With CMT

bull Correlation Between Clinical and Electrophysiological Phenotypes in a

Population of Patients With Neuropathy Charcot-Marie-Tooth Disease

Type 1A

bull Ascorbic Acid Treatment in CMT1A Trial (AATIC)

bull Phase II Randomized Placebo-controlled Trial in Patients With

Charcot-Marie-tooth Disease Type 1A

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Resource Centers for CMT

National CMT Resource Center

Charcot-Marie-Tooth Association

National Society for Genetic Counselors (NSGC)

Hereditary Disease Foundation

Hereditary Neuropathy Foundation

Alliance of Genetic Support Groups

Links to some CMT websitevideos

bull httpwwwnhsukvideopagescharcot-marie-tooth-

diseaseaspx

bull httpwwwmolgenuaacbeCMTMutationsHomeIPNcfm

bull httpwwwyoutubecomwatchv=Jspjvd43x7g

bull httpwwwbuffaloedunewsreleases201304056html

bull httpwwwncbinlmnihgovpmcarticlesPMC3058597

bull httpghrnlmnihgovgeneGJB1

bull httpwwwnaturecomncommsjournalv4n5fullncomms2

928htmlgenesandproteins

References

bull Cruse RP (2013) Hereditary primary motor sensory neuropathies including Charcot-Marie-Tooth disease Retrieved from

wwwuptodatecom

bull Houden H amp Reilly M (2006) Molecular Genetics of Autosomal-Dominant Demyelinating Charcot-Marie-Tooth Disease

NeuroMolecular Medicine (8 43-62)

bull Kedlaya D amp Calhoun J (2012) Charcot-Marie-Tooth Disease Clinical Presentation Retrieved from

httpemedicinemedscapecomarticle1232386-clinical

bull Martins Elisabeth N Branco Andreacute C Alvarenga Lecircnio S Uno Fausto Moraes Nilva B amp Belfort Jr Rubens (2000)

Charcot-Marie-Tooth disease and posterior scleritis a case report Arquivos Brasileiros de Oftalmologia 63(5) 413-415

Retrieved November 10 2013 from httpwwwscielobrscielophpscript=sci_arttextamppid=S0004-

27492000000500016amplng=enamptlng=en 101590S0004-27492000000500016

bull Suter U amp Scherer SS (2003) Disease mechanism in inherited neuropathies Nature Reviews Neuroscience (4 714-726)

bull Szigeti K Garcia CA amp Lupski JR (2006) Charcot-Marie-Tooth disease and related hereditary polyneuropathies Molecular

diagnostics determine aspects of medical management Genetics in Medicine (8 86-92) Retrieved from

httpwwwnaturecomgimjournalv8n2fullgim200614ahtml

bull httpstructbiovanderbiltedusandersResearch_Julia_Ver_1Researchhtml

bull Exp Neurol 2009 Aug218(2)268-73 doi 101016jexpneurol200905003 Epub 2009 May 8Role of mitofusin 2 mutations in

the physiopathology of Charcot-Marie-Tooth disease type 2ACartoni R Martinou JC

bull httpwwwclarksnutritioncomnsDisplayMonographaspStoreID=2691B1FE187D41ACB869A85CA5957A0AampDocID=condition-

charcotmarietooth