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Transcript of Charcot Marie Tooth · PDF file• First identified in 1886 by Martin Charcot, Pierre Marie...

  • 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