Charcot-Marie-Tooth Disease

By Eleanor R. Hethcox, ACNP-BC

Charcot-Marie-Tooth Disease

One of the most common inherited neurological disorders

Prevalence is 17-40:100,000 world wide

Affecting approximately 1 in 2,500 people in the U.S.

Affects male and females and all cultures.

First identified in 1886 by Martin Charcot, Pierre Marie and

Howard Henry Tooth

AKA Hereditary Motor and Sensory Neuropathy (HMSN)

or peroneal muscular atrophy

Affects peripheral nerves specifically related to the

myelin sheath and axons

Charcot-Marie-Tooth Disease

Many forms of CMT exist (CMT1,2,3,4,X)

Normal life expectancy; CMT is not fatal.

Onset of symptoms is most often in adolescence or early

adulthood.

Progression of symptoms is very gradual.

Slow progressing weakness beginning in the distal limb

muscles generally is noted. Usually starts in lower

extremities before it starts in the upper extremities.

Severity of symptoms may vary greatly among affected

individuals

Types of Hereditary Neuropathies

Charcot-Marie-Tooth Disease

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

http://www.mdnsw.org.au/old/FactsSheetsCMT.htm

Axons

Functions of the Myelin Sheath

Normal function of axon and myelin sheath

Classification of CMT

Myelin vs. Axon

Demyelinating:

HMSN/CMT type 1

Intermediate

Axonal: HMSN/CMT

type 2

Peripheral Neuropathy

CMT Clinico-electrophysiological Evaluation

CMT Inheritance Patterns

Extensive underling genetic heterogeneity

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.)

More than 40 genes have been implicated as causes of

the various forms of CMT.

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 & assoc. mutations each accounted for

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)

17p11;AD First decade Distal Weakness 15-20 m/s

CMT 1B (P0-

MPZ)

1q22;AD First decade Distal Weakness

CMT Types Continued

CMT

Type

Chromosome

/Inheritance

Pattern

Age of

Onset

Clinical Features Average

NCV

CMT 1D 10q21; AD 1st decade Distal weakness 15-20 m/s

CMT 1E 17p11; AD 1st decade Distal weakness 15-20 m/s

CMT 1F 8p21; AD 1st decade Distal weakness 15-20 m/s

CMT X Xq13; XD 2nd decade Distal weakness 25-40 m/s

CMT 2A 1p36; AD 10 y Distal weakness > 38 m/s

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 & distal weakness

> 50 m/s

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

Axon loss;

normal

CMT 2E 8p21;AD 10-30y Distal weakness, lower limb predominantly

Axon

loss;normal

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

loss;normal

CMT 2K 8q13-q21; AR < 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 < 10 m/s

CMT types Continued

CMT type Chromosome/inheritance

pattern

Age of onset Clinical features Average NCV

Congenital

hypomyelination

P0, EGR2 or PMP-22

AR

Birth Severe weakness < 10 m/s

CMT 4A 8q13; AR Childhood Distal weakness Slow

CMT 4B

(myotubular in-related

protein 2)

11q23; AR 2-4y Distal and proximal

weakness

Slow

CMT 4C 5q23; AR 5-15y Delayed walking 14-32 m/s

CMT 4D (Lom)

(N-myc Downstream-

regulated Gene 1)

8q24; AR 1-10y Distal muscle wasting,

foot and hand

deformities

10-20 m/s

CMT 4E (EGR2) 10q21; AR Birth Infant hypotonia 9-20 m/s

CMT 4G 10q23; AR 8-16y Distal weakness 9-20 m/s

CMT 4H 12p11,21-q13,11;AR 0-2y Delayed walking 9-20 m/s

CMT 4F 19q13;AR 1-3y Motor delay absent

CMT Types (AD, X-linked, AR)

CMT 2D

CMT 2E

CMT 2F

CMT 2G

CMT 2H

CMT 2I

CMT 2J

CMT 2K

CMT 2L

CMT R-Ax

(Ouvrier)

CMT 1A*

CMT 1B*

CMT 1C

CMT 1D

CMT 1E

CMT 1F

CMT X*

CMT 2A*

CMT 2B

CMT 2C

CMT R-Ax

(Moroccan)

Cowchock

syndrome

HNPP* (tomaculousneuropathy)

DSS

Congenital

hypomyelination

(CH)

CMT 4A

CMT 4B

CMT 4C

CMT 4D

CMT 4E

CMT 4G

CMT 4H

CMT 4F

Most common CMT/ CMT linked types

CMT1A

CMT1B

CMT X1

CMT2A

HNPP* (linked to CMT, but not a type of

CMT)

These types occur most

commonly.

CMT Type 1 A

PMP22

Genetics of CMT1 demyelinating

Caused by

mutations in genes

that are expressed

in Schwann cells

Exhibit AD, AR and

X-linked inheritance

Subdivided in types

A,B,C,etc.

CMT Type 1A Pedigree

Autosomal Dominant Inheritance

CMT 1A Autosomal Dominant Form

Most common type of CMT

PMP22 (peripheral myelin

protein) a hydrophobic 22-

kDa glycoprotein of 160 aa

Largely unknown, but

thought to have a role in

the initiation of myelin

spirals, regulation of

growth & differentiation of

Schwann cells and control

of thickness and stability of

myelin sheaths

CMT1A PMP22 gene

CMT 1A

Duplication of PMP-22

Chromosome affected

17p11

Autosomal Dominant

Age of Onset first

decade of life

Clinical features

distal weakness

Average NCV is 15-20

m/s

CMT Type 1B

Gene Myelin Protein Zero

Charcot Marie Tooth 1B

MPZ or Myelin Protein Zero

Normal function of MPZ is that of an adhesion molecule

Plays a role in myelin compaction

Charcot Marie Tooth 1B (CMT 1B)

Autosomal Dominant

Caused by mutations in the gene that carries the

instructions for manufacturing the myelin protein zero (P0).

Chromosome 1q22

Age of onset first decade

Distal weakness

Avg NCV < 20 m/s

Less common than CMT1A

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

CMT1 cases

CMT X1

Other Subtypes: 2,3,Cowchock syndrome, 5

CMT X1

X-linked Dominant inheritance

Age of Onset is in the second decade of life

Clinical features include distal weakness

Average NCV 25-40 m/s

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

aka connexin 32 gene on chromosome Xq13

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

homeostasis of myelinated axons

CMT X1

Gene is expressed in myelinating Schwann cells, but not

incorporated into the myelin sheath.

Both sexes are affected; symptoms more prominent in

boys.

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

Less common features include tremor, hand weakness and

sensorineural deafness.

Demyelina