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Charcot-Marie-Tooth Disease
Updated: Sep 9, 2009
Introduction
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).
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 18,9 - 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 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 29,13,14,15 - 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 416,17 - These also are demyelinating neuropathies.
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).
Clinical
History
- Patients have a significant family history. This history varies depending on the inheritance and penetrance pattern of the particular disorder (see Table). Spontaneous mutations also have been reported.
- Slowly progressing weakness beginning in the distal limb muscles generally is noted; it typically occurs in the lower extremities before it affects the upper ones. A subgroup of patients with Charcot-Marie-Tooth type 1A may present with proximal muscle wasting and weakness.
- Onset usually occurs in the first 2 decades of life.
- Patients initially may complain of difficulty walking and frequent tripping due to foot and distal leg weakness. Frequent ankle sprains and falls are characteristic.
- Parents may report that a child is clumsy or simply not very athletic.
- As weakness becomes more severe, foot drop commonly occurs. Steppage (that is, gait in which the individual must lift the leg in an exaggerated fashion to clear the foot off of the ground) also is common.
- Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavus. Symptoms related to structural foot abnormalities include calluses, ulcers, cellulitis, and lymphangitis.
- Hand weakness results in complaints of poor finger control, poor handwriting, difficulty using zippers and buttons, and clumsiness in manipulating small objects.
- Patients usually do not complain of numbness. This may be because patients with CMT disease never had normal sensation and, therefore, simply do not perceive their lack of sensation.
- Pain (musculoskeletal and neuropathic types) may be present. Muscle cramping is a common complaint.20
- Autonomic symptoms usually are absent, but a few men with CMT disease have reported impotence.
Physical
- 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 Charcot-Marie-Tooth disease include the following:
- Pes cavus (high-arch foot), probably analogous to the development of claw hand in ulnar nerve lesion, has a 25% occurrence rate in the first decade of life and a 67% occurrence rate in later decades. Other foot deformities also can occur (see Image 1).
- Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT type 1.
- Deep tendon reflexes (DTRs) are markedly diminished or are absent.
- Vibration sensation and proprioception are significantly decreased, but patients usually have no sensory symptoms.
- Patients may have sensory gait ataxia, and a Romberg test usually is positive.
- Sensation of pain and temperature is usually intact.
- Essential tremor is present in 30-50% of patients with CMT disease.
- Sensory neuronal hearing loss is observed in 5% of patients.
- Enlarged and palpable peripheral nerves are common.
- Phrenic nerve involvement with diaphragmatic weakness is rare but has been described.
- Vocal cord involvement and hearing loss can occur in rare forms of CMT disease.
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 (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 |
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 hereditary motor and sensory neuropathy (HMSN) 3 | P0; AR | 2 y | Severe weakness | <10 m/s |
Congenital | P0, EGR2 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 (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 |
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 |
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 hereditary motor and sensory neuropathy (HMSN) 3 | P0; AR | 2 y | Severe weakness | <10 m/s |
Congenital | P0, EGR2 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 (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
- HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy)1
- HMSN I (ie, CMT 1)8,9
- 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 cerebral spinal fluid (CSF) protein
- Hereditary motor and sensory neuropathy with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)
- HMSN II (ie, CMT 2)9,13,15
- CMT 2A - Band 1p35-36; typical type; no enlarged nerves; later onset of symptoms; feet are more severely affected than hands
- CMT 2B14,30 - 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) - Normal upper limbs and no sensory symptoms
- HMSN II (ie, CMT 2)9,13,15
- Roussy-Levy syndrome - Autosomal dominant with essential tremor
- HMSN VI - With optic atrophy
- HMSN VII - With retinitis pigmentosa
- Prednisone-responsive hereditary neuropathy
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| References |
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Further Reading
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Keywords
Charcot-Marie-Tooth, CMT, CMT 1, CMT 2, hereditary motor and sensory neuropathy, HMSN, peroneal muscular atrophy, PMA, peroneal progressive muscular atrophy, peroneal muscular atrophy with thickened nerves, Hoffman disease, Charcot-Marie-Tooth-Hoffman disease
