What causes Charcot-Marie-Tooth disease (CMT)?

Updated: Jun 23, 2021
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Elizabeth A Moberg-Wolff, MD  more...
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Answer

Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM). More than 900 mutations in 60 genes are associated with the disease. [47, 48] The list can be found at http://www.molgen.vib-ua.be/CMTMutations/Home/IPN.cfm.

Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison (Open Table in a new window)

CMT Type

Chromosome; Inheritance Pattern

Age of Onset

Clinical Features

Average NCVs§

CMT-1A (PMP-22 dupl.)

17p11.2; AD*

First decade

Distal weakness

15-20 m/s

CMT-1B (P0 -MPZ)**

1q23.3; AD

First decade

Distal weakness

< 20 m/s

CMT-1C (non-A, non-B) (LITAF)

16p13.13;AD

Second decade

Distal weakness

26-42 m/s

CMT-1D (EGR-2)#

10q21.3; AD

First decade

Distal weakness

15-20 m/s

CMT-1E (PMP22)

17p11.2; AD

First decade

Distal weakness, deafness

15-20 m/s

CMT-1F (NEFL)

8p21.2; AD

First decade

Distal weakness

15-20 m/s

CMT-X (connexin-32) [49, 50, 51, 52]

Xq13; XD

Second decade

Distal weakness

25-40 m/s

CMT-2A

1p36; AD

10 y

Distal weakness

>38 m/s

CMT-2B

3q21; AD

Second decade

Distal weakness,

sensory loss, skin ulcers

Axon loss; Normal

CMT-2C

12q23-q24, AD

First decade

Vocal cord, diaphragm, and

distal weakness

>50 m/s

CMT-2D

7p14; AD

16-30 y

Distal weakness, upper limb predominantly

Axon loss; N††

CMT-2E

8p21; AD

10-30 y

Distal weakness, lower limb predominantly

Axon loss; N

CMT-2F

7q11-q21; AD

15-25 y

Distal weakness

Axon loss; N

CMT-2G

12q12-q13; AD

9-76 y

Distal weakness

Axon loss; N

CMT-2H

8q21; AD

15-25 y

Distal weakness, pyramidal features

Axon loss; N

CMT-2I

1q23; AD

47-60 y

Distal weakness

Axon loss; N

CMT-2J

1q23; AD

40-50 y

Distal weakness, hearing loss

Axon loss; N

CMT-2K

8q13-q21; AD

< 4 y

Distal weakness

Axon loss; N

CMT-2L

12q24; AD

15-25 y

Distal weakness

Axon loss; N

CMT–R-Ax (Ouvrier)

AR

First decade

Distal weakness

Axon loss; N

CMT–R-Ax (Moroccan)

1q21; AR

Second decade

Distal weakness

Axon loss; N

Cowchock syndrome

Xq24-q26

First decade

Distal weakness, deafness, mental retardation

Axon loss; N

HNPP|| (PMP-22 deletion) [53]

or tomaculous neuropathy

17p11; AD

All ages

Episodic weakness and numbness

Conduction Blocks

Dejerine-Sottas-syndrome (DSS) or HMSN-3 [54]

P0; AR

PMP-22; AD

8q23; AD

2 y

Severe weakness

< 10 m/s

Congenital

hypomyelination (CH)

P0, EGR-2 or PMP-22

AR

Birth

Severe weakness

< 10 m/s

CMT-4A [55]

8q13; AR

Childhood

Distal weakness

Slow

CMT-4B

(myotubularin- related

protein 2) [56, 57]

11q23; AR

2-4 y

Distal and proximal

weakness

Slow

CMT-4C

5q23; AR

5-15 y

Delayed walking

14-32 m/s

CMT-4D (Lom)

(N-myc downstream-

regulated gene 1)

8q24; AR

1-10 y

Distal muscle wasting, foot and hand deformities

10-20 m/s

CMT-4E (EGR-2)

10q21; AR

Birth

Infant hypotonia

9-20 m/s

CMT-4G

10q23.2; AR

8-16 years

Distal weakness

9-20 m/s

CMT-4H

12p11.21-q13.11; AR

0-2 years

Delayed walking

9-20 m/s

CMT-4F

19q13; AR

1-3 y

Motor delay

Absent

*Autosomal dominant

†Autosomal recessive

‡X-linked dominant

§Nerve conduction velocities

||Hereditary neuropathy with liability to pressure palsy

¶Peripheral myelin protein

#Early growth response

**Myelin protein zero

††Normal

The above classification is the most specific, up-to-date, and comprehensive classification for Charcot-Marie-Tooth disease (CMT). In the past, CMT was classified as hereditary motor and sensory neuropathy (HMSN). [58, 59] Hereditary neuropathy with diffusely slow nerve conduction velocity (hypertrophic neuropathy) is HMSN-I.

  • HMSN-I (CMT-1) with different subclassifications. [60]

  • HMSN-III (Dejerine-Sottas disease, hypertrophic neuropathy of infancy, congenital hypomyelinated neuropathy) - Autosomal recessive inheritance

  • HMSN-IV (Refsum syndrome - phytanic acid excess) - Autosomal recessive inheritance—tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebrospinal fluid (CSF) protein

  • Hereditary motor and sensory neuropathy with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type) [61] :

    • HMSN-II (CMT-2)

      • CMT-2A - Chromosome 1(p35-36) - Typical type, no enlarged nerves, later onset of symptoms, feet more severely affected than hands

      • CMT-2B - Chromosome 3(q13-22) - Typical type with axonal spheroids

      • CMT-2C - Not linked to any known loci; diaphragm and vocal cord weakness

      • CMT-2D - Chromosome 7(p14) - Muscle weakness and atrophy is more severe in hands than feet

      • Autosomal recessive CMT-2

    • HMSN-V (ie, spastic paraplegia) - Normal upper limbs and no sensory symptoms

  • Roussy-Levy syndrome - Autosomal dominant with essential tremor

  • HMSN-VI - With optic atrophy

  • HMSN-VII - With retinitis pigmentosa

  • Prednisone-responsive hereditary neuropathy

A study by Rose et al of 30 pediatric patients with CMT indicated that a significant association exists between functional ankle instability in children with disease and cavus foot structure, female sex, and impaired balance. [62]


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