Charcot-Marie-Tooth Disease

Updated: Aug 03, 2017
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Vinod K Panchbhavi, MD, FACS  more...
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Overview

Background

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. It is characterized by inherited neuropathies without known metabolic derangements. [1, 2]

In 1886, Professor Jean Martin Charcot of France (1825-1893) and his student Pierre Marie (1853-1940) published the first description of distal muscle weakness and wasting beginning in the legs, calling it peroneal muscular atrophy.

Howard Henry Tooth (1856-1926) described the same disease in his Cambridge dissertation in 1886, calling the condition peroneal progressive muscular atrophy. Tooth was the first to attribute symptoms correctly to neuropathy rather than to myelopathy, as physicians previously had done.

In 1912, Hoffman identified a case of peroneal muscular atrophy with thickened nerves. This disease was referred to as Hoffman disease and later was known as Charcot-Marie-Tooth-Hoffman disease.

In 1968, CMT disease was subdivided into two types, CMT 1 and CMT 2, on the basis of pathologic and physiologic criteria. It has been subdivided further on the basis of the genetic cause of the disease. With the advent of genetic testing, it is likely that all of the diseases currently falling under the heading of CMT syndrome will eventually become distinguishable. [3]

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Pathophysiology

CMT disease is a heterogeneous group of genetically distinct disorders with similar clinical presentations. [1]  Its genetic spectrum spans more than 80 genes. [4] Gene discovery has been revolutionized by new high-throughput molecular technologies. [5]  CMT disease is divided into several types, as follows.

CMT 1

CMT type 1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP22) gene. [6, 7] Mutations in the gene encoding the major PNS myelin protein, myelin protein zero (MPZ), account for 5% of patients with CMT disease. The mutation results in abnormal myelin that is unstable and spontaneously breaks down.

This process results in demyelination, leading to uniform slowing of conduction velocity. Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. However, a study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT 1A are caused by loss of or damage to large-diameter motor and sensory axons. [8, 9, 10]

Pain and temperature sensations usually are not affected because they are carried by unmyelinated (type C) nerve fibers. In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons. These changes cause what is referred to as an onion bulb appearance.

CMT 2

CMT type 2 primarily is a neuronal (ie, axonal) disorder, not a demyelinating disorder. [7, 11, 12, 13] It results in peripheral neuropathy through direct axonal death and Wallerian degeneration.

CMT 3

Characterized by infantile onset, CMT type 3 (also known as Dejerine-Sottas disease) results in severe demyelination with delayed motor skills; it is much more severe than CMT type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination.

CMT X and CMT 4

CMT X (X-linked CMT) and CMT 4 also are demyelinating neuropathies. [14, 15]

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Etiology

Hereditary motor and sensory neuropathies (HMSNs) are classified by Online Mendelian Inheritance in Man (OMIM). A broad division may be made between HMSNs with diffusely slow nerve conduction velocity and those with normal or borderline abnormal nerve conduction velocity. [16]

HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy)

HMSN I (ie, CMT 1) includes the following subtypes [6, 7] :

  • CMT 1A [9, 10, 17, 18, 19] - Autosomal dominant band 17p11.2-12 is most common; milder than CMT 1B
  • CMT 1B - Autosomal dominant band 1q21-25
  • CMT 1C - Unknown autosome
  • CMT X1 - X-linked dominant band Xq13-21
  • CMT X2 and CMT X3 - X-linked recessive
  • Autosomal recessive CMT 1 - Arm 8q

HMSN III (Dejerine-Sottas disease, hypertrophic neuropathy of infancy, congenital hypomyelinated neuropathy) is inherited in an autosomal recessive manner.

HMSN IV (Refsum syndrome, phytanic acid excess) has an autosomal recessive inheritance and is characterized by a tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebrospinal fluid (CSF) protein.

HMSN with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)

HMSN II (ie, CMT 2) includes the following subtypes [7, 11, 13] :

  • CMT 2A - Band 1p35-36; typical type; no enlarged nerves; later onset of symptoms; feet are more severely affected than hands
  • CMT 2B [12, 20] - Band 3q13-22; typical type with axonal spheroids
  • CMT 2C - Not linked to any known loci; diaphragm and vocal cord weakness
  • CMT 2D - Band 7p14; muscle weakness and atrophy more severe in hands than in feet
  • Autosomal recessive CMT 2

HMSN V (ie, spastic paraplegia) is characterized by normal upper limbs and the absence of sensory symptoms. Roussy-Levy syndrome has an autosomal dominant inheritance and is characterized by essential tremor. HMSN VI is characterized by optic atrophy. HMSN VII is associated with retinitis pigmentosa. Prednisone-responsive hereditary neuropathy is the final HMSN of this type.

Genetic and clinical features of CMT disorders are listed in Table 1 below.

Table 1. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison (Open Table in a new window)

</tbody>

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

</td></tr>

CMT 1C (non A, non B)

16p13;AD

Second decade

Distal weakness

26-42 m/s

CMT 1D (early growth response [EGR]-2) [#] [21]

10q21; AD

First decade

Distal weakness

15-20 m/s

CMT 1E

17p11; AD

First decade

Distal weakness, deafness

15-20 m/s

CMT 1F

8p21; AD

First decade

Distal weakness

15-20 m/s

CMT X (Connexin-32) [22, 23, 24, 25, 26]

Xq13; XD

Second decade

Distal weakness

25-40 m/s

CMT 2A

1p36; AD

10 y

Distal weakness

>38 m/s

CMT 2B

3q; 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

?; AR

15-25 y

Distal weakness, Pyramidal features

Axon loss; N

CMT 2I

1q22; AD

47-60 y

Distal weakness

Axon loss; N

CMT 2J

1q22; AD

40-50 y

Distal weakness, hearing loss

Axon loss; N

CMT 2K

8q13-q21; AR

<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)

Or tomaculous neuropathy

17p11; AD

All ages

Episodic weakness and numbness

Conduction Blocks

Dejerine-Sottas syndrome (DSS) or hereditary motor and sensory neuropathy (HMSN) 3

P0; AR

PMP-22; AD

8q23; AD

2 y

Severe weakness

</td></tr>

Congenital

hypomyelination (CH)

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) [15]

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 (EGR2)

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

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Epidemiology

United States statistics

The prevalence of CMT disease is 1 person per 2500 population, or about 125,000 people in the United States. The incidence of CMT 1 is 15 persons per 100,000 population; the incidence of CMT 1A is 10.5 persons per 100,000 population, or 70% of CMT 1. The incidence of CMT 2 is 7 persons per 100,000 population. Persons with CMT X represent at least 10-20% of people with the CMT syndrome.

International statistics

In Japan, the prevalence is reported to be 10.8 cases per 100,000 population; in Italy, it is reported to be 17.5 cases per 100,000 population; and in Spain, it is 28.2 cases per 100,000 population. [27, 28]

According to a Norwegian genetic epidemiologic study, CMT disease is the most common inherited disorder of the peripheral nervous system, with an estimated prevalence of 1 in 1214. CMT 1 and CMT 2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ, and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de novo mutations in CMT families was estimated to be 22.7%. Genotype-phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described. [29]

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Prognosis

Prognoses for the different types of CMT disease vary and depend on clinical severity. Generally, CMT disease is a slowly progressive neuropathy that causes eventual disability secondary to distal muscle weakness and deformities. In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties. CMT disease does not usually shorten the expected life span.

Shy et al developed the CMT neuropathy score, which is a modification of the total neuropathy score. [30] This has been shown to be a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies of and clinical trials related to CMT disease. [19]

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Patient Education

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance patterns, and implications of genetic disorders in order to help them make informed medical and personal decisions. Offer patients with CMT disease genetic counseling so that they can make informed decisions regarding the potential risk of passing the disease to their children. [18, 31]

Drugs and medications, such as vincristine, isoniazid, paclitaxel, cisplatin, and nitrofurantoin, are known to cause nerve damage and should be avoided.

Routine exercise within the individual's capability is encouraged; many individuals remain physically active. [32] No specific activity limitation is recommended.

Obesity should be avoided, because it makes walking more difficult.

Daily heel-cord stretching exercises are warranted to prevent Achilles tendon shortening.

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