Charcot-Marie-Tooth Disease

Updated: Feb 06, 2023
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Vinod K Panchbhavi, MD, FACS, FAOA, FABOS, FAAOS  more...
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Practice Essentials

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. It is characterized by inherited neuropathies without known metabolic derangements. [1, 2]  These disorders are also known as hereditary motor and sensory neuropathies (HMSNs); they are distinct from hereditary sensory neuropathies (HSNs) and hereditary motor neuropathies (HMNs).

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]

Although all routine laboratory tests are normal in individuals with CMT disease, special genetic tests are available for some types. (See Workup.) Electromyography (EMG) and nerve conduction studies should be performed first if CMT disease is suggested. High-resolution ultrasonography (US) of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis in some cases. Magnetic resonance imaging (MRI) of lower-limb muscles may be used to follow disease progression. Nerve biopsy is rarely indicated but is sometimes performed in cases of diagnostic dilemmas.

Currently, no proven medical treatment exists to reverse or slow the natural disease process for the underlying disorder. (See Treatment.) Orthopedic surgery is required to correct severe pes cavus deformities, scoliosis, and other joint deformities. Treatment is determined by the age of the patient and the cause and severity of the deformity. Surgical procedures consist of the following three types: (1) soft-tissue procedures (plantar fascia release, tendon release or transfer); (2) osteotomy (metatarsal, midfoot, calcaneal); and (3) joint-stabilizing procedures (triple arthrodesis).



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 type 1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP22) gene. [6, 7, 8] 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 et al suggested that neurologic dysfunction and clinical disability in CMT 1A are caused by loss of or damage to large-diameter motor and sensory axons. [9, 10, 11]

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. [12] 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 type 2 primarily is a neuronal (ie, axonal) disorder, not a demyelinating disorder. [7, 13, 14, 15] It results in peripheral neuropathy through direct axonal death and wallerian degeneration. It has been associated with mutations in the ATP1A1 gene. [16]


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. [17, 18]  CMT X has been associated with mutations in the PRPS1 gene. [19]



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. [20]

HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy)

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

  • CMT 1A [10, 11, 21, 22, 23] - 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, 13, 15] :

  • CMT 2A - Band 1p35-36; typical type; no enlarged nerves; later onset of symptoms; feet are more severely affected than hands
  • CMT 2B [14, 24] - 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)

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

< 20 m/s

CMT 1C (non A, non B)


Second decade

Distal weakness

26-42 m/s

CMT 1D (early growth response [EGR]-2) [#] [25]

10q21; AD

First decade

Distal weakness

15-20 m/s


17p11; AD

First decade

Distal weakness, deafness

15-20 m/s


8p21; AD

First decade

Distal weakness

15-20 m/s

CMT X (Connexin-32) [26, 27, 28, 29, 30]

Xq13; XD

Second decade

Distal weakness

25-40 m/s


1p36; AD

10 y

Distal weakness

>38 m/s


3q; AD

Second decade

Distal weakness,

sensory loss, skin ulcers

Axon loss; Normal


12q23-q24, AD

First decade

Vocal cord, diaphragm, and

distal weakness

>50 m/s


7p14; AD

16-30 y

Distal weakness, upper limb predominantly

Axon loss; N††


8p21; AD

10-30 y

Distal weakness, lower limb predominantly

Axon loss; N


7q11-q21; AD

15-25 y

Distal weakness

Axon loss; N


12q12-q13; ?AD

9-76 y

Distal weakness

Axon loss; N


?; AR

15-25 y

Distal weakness, Pyramidal features

Axon loss; N


1q22; AD

47-60 y

Distal weakness

Axon loss; N


1q22; AD

40-50 y

Distal weakness, hearing loss

Axon loss; N


8q13-q21; AR

< 4 y

Distal weakness

Axon loss; N


12q24; AD

15-25 y

Distal weakness

Axon loss; N

CMT R-Ax (Ouvrier)


First decade

Distal weakness

Axon loss; N

CMT R-Ax (Moroccan)

1q21; AR

Second decade

Distal weakness

Axon loss; N

Cowchock syndrome


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

< 10 m/s


hypomyelination (CH)

P0, EGR2 or PMP-22



Severe weakness

< 10 m/s


8q13; AR


Distal weakness



(Myotubular in-related

protein-2) [18]

11q23; AR

2-4 y

Distal and proximal




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


10q21; AR


Infant hypotonia

9-20 m/s


10q23.2; AR

8-16 years

Distal weakness

9-20 m/s


12p11.21-q13.11; AR

0-2 years

Delayed walking

9-20 m/s


19q13; AR

1-3 y

Motor delay


*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




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. [31, 32]

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. [33]



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. Motor performance deterioration in CMT 1A appears to accelerate after age 50 years. [34] 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. [35] 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. [23]


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. Genetic counseling should be offered to patients with CMT disease so that they can make informed decisions regarding the potential risk of passing the disease to their children. [22, 36]

Certain drugs and medications (eg, 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. [37] 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.