eMedicine Specialties > Physical Medicine and Rehabilitation > Peripheral Neuropathy
Charcot-Marie-Tooth Disease
Updated: Feb 16, 2009
Introduction
Background
Charcot-Marie-Tooth disease (CMT) is the most common inherited neurologic disorder. CMT is characterized by inherited neuropathies without known metabolic derangements. 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 correctly attribute the disorder's symptoms to neuropathy rather than to myelopathy, as physicians had done before him. 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 was subdivided into 2 types, CMT-1 and CMT-2, based on pathologic and physiologic criteria. CMT has been further subdivided, based on the genetic cause of the disease. With the advent of genetic testing, all of the different diseases that fall under the heading of CMT syndrome eventually are likely to become distinguishable.
Related eMedicine topics:
Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies
Charcot-Marie-Tooth Disease [Orthopedic Surgery]
Hereditary Neuropathies of the Charcot-Marie-Tooth Disease Type
Pathophysiology
Charcot-Marie-Tooth disease (CMT) is actually a heterogeneous group of genetically distinct disorders with a similar clinical presentation. CMT-1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP-22) gene. Mutations in the gene encoding the major peripheral nervous system myelin protein, myelin protein zero (MPZ), account for 5% of patients with CMT. 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. A study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT-1A are caused by loss or damage to large-diameter motor and sensory axons.1 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 is primarily a neuronal (ie, axonal) disorder, not a demyelinating disorder. Type 2 results in peripheral neuropathy through direct axonal death and wallerian degeneration. CMT-3 (also known as Dejerine-Sottas disease) is characterized by infantile onset. Type 3 results in severe demyelination with delayed motor skills and is a much more severe form 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 are also demyelinating neuropathies.
Frequency
United States
The prevalence of Charcot-Marie-Tooth disease (CMT) is 1 person per 2500 population, or about 125,000 patients in the US. CMT-1 incidence is 15 persons per 100,000 population. CMT-1A incidence is 10.5 persons per 100,000 population, or 70% of CMT-1 cases. CMT-2 incidence is 7 persons per 100,000 population. CMT-X represents at least 10-20% of persons with the CMT syndrome.
International
In Japan, the prevalence of Charcot-Marie-Tooth disease is reportedly 10.8 cases per 100,000 population. In Italy, the prevalence is reported to be 17.5 cases per 100,000 population, and in Spain, it is 28.2 cases per 100,000 population.
Mortality/Morbidity
Morbidity in Charcot-Marie-Tooth disease is mainly secondary to distal muscle weakness and foot deformities.2,3 In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties.
Race
No race predilection is recognized in Charcot-Marie-Tooth disease.
Sex
There is no known sex predilection in Charcot-Marie-Tooth disease.
Age
The age of presentation for Charcot-Marie-Tooth disease (CMT) varies depending on the type of CMT. Please refer to the table under Causes.
Clinical
History
- Patients usually have a significant family history of Charcot-Marie-Tooth disease (CMT). This history varies, depending on the inheritance and penetrance pattern of the particular disorder. Spontaneous mutations also have been reported.
- Slow progressing weakness beginning in the distal limb muscles, typically in the lower extremities before the upper extremities, generally is noted.3 A subgroup of patients with CMT-1A can present with proximal muscle wasting and weakness.
- Onset usually is in the first 2 decades of life.
- Patients' initial complaints may be difficulty walking and frequent tripping because of foot and distal leg weakness. Frequent ankle sprains and falls are characteristic.3
- Parents may report that a child is clumsy or simply not very athletic.
- As weakness becomes more severe, foot drop commonly occurs. Steppage (ie, gait in which patient must lift the leg in an exaggerated fashion to clear the foot off the ground) also is common.3
- Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavus.2,3 Symptoms related to structural foot abnormalities include calluses, ulcers, cellulitis, or lymphangitis.
- Hand weakness results in complaints of poor finger control, poor handwriting, difficulty using zippers and buttons, and clumsiness in manipulating small objects.4,5
- Patients usually do not complain of numbness. This phenomenon may be due to the fact that CMT patients will have never had normal sensation and therefore, simply do not perceive their lack of sensation.
- Musculoskeletal and neuropathic types of pain may be present. Muscle cramping is a common complaint.
- Autonomic symptoms usually are absent, but a few men with CMT have reported impotence.
Physical
- In patients with Charcot-Marie-Tooth disease (CMT), distal muscle wasting may be noted in the legs, resulting in the characteristic stork leg or inverted champagne bottle appearance.
- Bony abnormalities commonly seen in long-standing CMT include the following:
- In 25% of cases, pes cavus (high-arch foot), which is probably analogous to the development of claw hand in ulnar nerve lesion, occurs in the first decade of life; in 67% of cases it arises in later decades. Other foot deformities also can occur (see image below and Image 1).2,3
- Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT-1.
- Deep tendon reflexes (DTRs) are markedly diminished or absent.
- Vibration sensation and proprioception are decreased significantly, although patients usually have no sensory symptoms.
- Patients may have sensory gait ataxia, and Romberg test is usually positive.
- Sensation of pain and temperature usually is intact.
- Essential tremor is present in 30-50% of CMT patients.
- Sensory neuronal hearing loss is observed in 5% of patients.6,7
- Enlarged and palpable peripheral nerves are common.
- Phrenic nerve involvement with diaphragmatic weakness is rare, but it has been described.
- Vocal cord involvement and hearing loss can occur in rare forms of CMT.6,7
Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
Causes
Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM).Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison
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Table
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 (EGR-2)# | 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) | 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, | Axon loss; Normal |
CMT-2C | 12q23-q24, AD | First decade | Vocal cord, diaphragm, and | >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) | 17p11; AD | All ages | Episodic weakness and numbness | Conduction Blocks |
Dejerine-Sottas-syndrome (DSS) or HMSN-3 | P0; AR | 2 y | Severe weakness | <10 m/s |
Congenital | P0, EGR-2 or PMP-22 | Birth | Severe weakness | <10 m/s |
CMT-4A | 8q13; AR | Childhood | Distal weakness | Slow |
CMT-4B | 11q23; AR | 2-4 y | Distal and proximal | Slow |
CMT-4C | 5q23; AR | 5-15 y | Delayed walking | 14-32 m/s |
CMT-4D (Lom) | 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 |
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 (EGR-2)# | 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) | 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, | Axon loss; Normal |
CMT-2C | 12q23-q24, AD | First decade | Vocal cord, diaphragm, and | >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) | 17p11; AD | All ages | Episodic weakness and numbness | Conduction Blocks |
Dejerine-Sottas-syndrome (DSS) or HMSN-3 | P0; AR | 2 y | Severe weakness | <10 m/s |
Congenital | P0, EGR-2 or PMP-22 | Birth | Severe weakness | <10 m/s |
CMT-4A | 8q13; AR | Childhood | Distal weakness | Slow |
CMT-4B | 11q23; AR | 2-4 y | Distal and proximal | Slow |
CMT-4C | 5q23; AR | 5-15 y | Delayed walking | 14-32 m/s |
CMT-4D (Lom) | 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). Hereditary neuropathy with diffusely slow nerve conduction velocity (hypertrophic neuropathy) is HMSN-I.
- HMSN-I (CMT-1) with different subclassifications
- 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)
- 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
- HMSN-II (CMT-2)
- Roussy-Levy syndrome - Autosomal dominant with essential tremor
- HMSN-VI - With optic atrophy
- HMSN-VII - With retinitis pigmentosa
- Prednisone-responsive hereditary neuropathy
More on Charcot-Marie-Tooth Disease |
 Overview: Charcot-Marie-Tooth Disease |
| Differential Diagnoses & Workup: Charcot-Marie-Tooth Disease |
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| Follow-up: Charcot-Marie-Tooth Disease |
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| References |
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Further Reading
Keywords
Charcot-Marie-Tooth disease, Charcot Marie Tooth, Charcot Marie Tooth disease, neuropathy, Charcot, Charcot Marie, pes cavus, connexin, Charcot Marie Tooth syndrome, hereditary motor sensory neuropathy, HMSN, peroneal muscular atrophy, PMA, CMT
