Charcot-Marie-Tooth Disease
- Author: Divakara Kedlaya, MBBS; Chief Editor: Jason H Calhoun, MD, FACS more...
Background
Charcot-Marie-Tooth (CMT) disease is the most common inherited neurologic disorder. CMT is characterized by inherited neuropathies without known metabolic derangements.[1, 2, 3, 4]
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 2 types, CMT 1 and CMT 2, based on pathologic and physiologic criteria. CMT disease has been subdivided further based on the genetic cause of the disease (see Table). See the images below.
Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A. 
Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A); compared with normal (B). With the advent of genetic testing, all of the diseases that fall under the heading of CMT syndrome are likely to eventually become distinguishable.
Recent studies
Cartwright et al characterized the ultrasound findings in peripheral nerves of patients with CMT 1B. Persons with CMT 1B were found to have larger median and vagus nerves than those of healthy individuals, but there was no difference seen in cranial nerve size between those patients with CMT 1B who had cranial neuropathies and those with CMT 1B who did not.[5]
Ward et al studied the long-term results of surgical reconstruction procedures for cavovarus foot deformity in 25 patients with CMT disease. The patients had undergone the procedure between 1970 and 1994 and were evaluated at a mean duration of follow-up of 26.1 years. The authors found that the use of soft-tissue procedures and first metatarsal osteotomy resulted in lower rates of degenerative changes and reoperations when compared to results obtained with triple arthrodesis.[6]
Burns et al examined 84 children (age range, 2-16 y) with CMT 1A to characterize hand strength and function in these patients, noting that the foot and leg are thought to be affected first, followed later by hand weakness and dysfunction. They found that hand weakness and dysfunction were present even at the earliest stages of the disease. Hand problems such as poor handwriting, weakness, pain, and sensory symptoms worsened with age. The authors noted that the hand is affected at all ages in children with CMT 1A and suggested that hand problems in these patients may be underrecognized in the early stages of disease, causing potential delay in therapy.[7]
Pathophysiology
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetically distinct disorders with similar clinical presentations.[1] The disease is divided into the following types:
CMT type 1 [8, 9]
This form of CMT disease is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP22) gene. 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.[10, 11, 12] 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 ofdemyelination 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 [9, 13, 14, 15]
This primarily is a neuronal (ie, axonal) disorder, not a demyelinating disorder. CMT type 2 results in peripheral neuropathy through direct axonal death and Wallerian degeneration.
CMT type 3 (also known as Dejerine-Sottas disease)
Characterized by infantile onset, this condition results in severe demyelination with delayed motor skills; it is much more severe than type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination.
CMT X (X-linked CMT) and CMT 4 [16, 17]
These also are demyelinating neuropathies.
Epidemiology
Frequency
United States
The prevalence of Charcot-Marie-Tooth (CMT) disease is 1 person per 2500 population, or about 125,000 people in the United States. The incidence of CMT type 1 is 15 persons per 100,000 population; the incidence of CMT type 1A is 10.5 persons per 100,000 population, or 70% of CMT type 1. The incidence of CMT type 2 is 7 persons per 100,000 population. Persons with CMT X represent at least 10-20% of people with the CMT syndrome.
International
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.[18, 19]
Mortality/Morbidity
Morbidity in Charcot-Marie-Tooth disease is mainly secondary to distal muscle weakness and foot deformities. In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties.
Age
The age of presentation varies depending on the type of Charcot-Marie-Tooth disease (see Table).
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| 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) | 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 | < 10 m/s |
| 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)[17] | 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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