Charcot-Marie-Tooth Disease

Stephen Marcaccio, M.D.
Andrew D. Sobel, M.D.

Basic Information

Definition

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of noninflammatory inherited peripheral neuropathies characterized by chronic motor and sensory polyneuropathy. It is the most common inherited neuromuscular disorder and, overall, one of the most common hereditary disorders (see also “Neuropathy, Hereditary”).

Synonyms

Peroneal muscular atrophy
Hereditary motor and sensory neuropathy (HMSN)
CMT

Epidemiology & Demographics

Prevalence

1:2500; CMT type 1 and type 2 are the major divisions with an estimated prevalence of 40 per 100,000

Predominant Age

Onset usually 10 to 20 years of age; may present in infants

Genetics

Transmission may be autosomal dominant, autosomal recessive, or X-linked, with some sporadic cases reported. Duplication of the gene for peripheral myelin protein 22 (PMP22) on chromosome 17 is the most common cause of CMT. X-linked mutations include changes in the GJB1 gene encoding connexin 32, a member of the gap junction gene family. CMT is classified into types 1 through 7 and is genetically heterogeneous with at least 43 CMT genes known.

Physical Findings & Clinical Presentation

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Despite variation in genetic causes, affected individuals tend to present with a homogenous clinical phenotype.
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Symptoms appear in the first decade of life in 60% of cases, but mild cases with later presentation are also observed.
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Symmetric, slowly progressive distal motor neuropathy resulting in weakness and atrophy in legs, often progresses to involve hands.
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High-arched feet (pes cavus) due to selective denervation of intrinsic foot musculature, claw toe deformities (Fig. E1), and hammer toes.
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Atrophy of the lower legs producing a “stork-like” appearance (muscle wasting does not involve the upper legs) (Fig. E2).
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Nerve and nerve root enlargement
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Most patients have no clinical sensory deficits, but if they exist, they are mild to moderate in distal distributions; painful paresthesias are even more uncommon.
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Decreased proprioception and weakness of ankle dorsiflexors often interfere with balance and gait (steppage gait). Ambulation is usually maintained throughout life.
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Deep tendon reflexes are commonly depressed or absent.
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Hearing loss and hip dysplasia are under-recognized manifestations.
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Has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS).

FIG.E1

A, Non–weight-bearing view of cavus and claw toe deformities in a patient with Charcot-Marie-Tooth disease. B, On weight-bearing view, plantar flexion of first ray is less noticeable, but clawed hallux remains, indicating fixed extension contracture at first metatarsophalangeal joint.

From Canale ST, Beaty JH: *Campbell’s operative orthopedics*, ed 11, Philadelphia, 2007, Mosby.

FIG.E2

Patient with Charcot-Marie-Tooth disease showing marked wasting of calf muscles and intrinsic foot muscles.

From Dubowitz V: *Muscle disorders in childhood,* London, 1995, Saunders.

Etiology

Genetic abnormalities cause defects in either peripheral nerve myelination or result in axonal degeneration. Mutations in one of several myelin genes result in defects in myelin structure, maintenance, and formation. Duplication of the PMP22 gene causes CMT1A, the most common type of hereditary motor sensory neuropathy (∼40% overall). INF₂ mutations appear to cause many cases of FSGS-associated CMT. GJB1 mutations appear to cause many cases of X-linked CMT.

Diagnosis

Differential Diagnosis

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Other inherited neuropathies.
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Acquired peripheral neuropathies such as toxic, metabolic, infectious, endocrine, inflammatory, immune-mediated, and nutritional polyneuropathies.

Workup

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Clinical diagnosis is based on family history, characteristic presentation, and findings on detailed physical and neurologic examination.
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Electrophysiologic studies are often diagnostic, with decreased conduction velocities and prolonged distal latencies noted in affected nerves (most commonly peroneal but also ulnar and median nerves).
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Genetic testing: PCR analysis (assess PMP22 mutations) and chromosome analysis (most common form demonstrates duplication on chromosome 17).
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Occasionally, a sural nerve biopsy is helpful in establishing diagnosis.

Treatment

Acute General Rx

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Symptomatic and supportive, managed by multidisciplinary team including physical and occupational therapy.
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Pes cavus: orthotics/inserts. Consider ankle-foot orthosis if foot drop develops.
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Some require crutches/cane for gait stability; <5% need wheelchair.
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Daily heel cord stretching exercises and hand grip exercises to improve or maintain strength in affected muscles.
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Musculoskeletal pain may respond to acetaminophen or NSAIDs; neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.

Chronic Rx

Occasionally, orthopedic surgery is required to correct severe pes cavus deformity or hip dysplasia. Avoiding obesity is essential as this makes walking difficult; avoiding potentially neurotoxic medications is also important, particularly Vinca alkaloids.

Disposition

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Disability is usually compatible with a long life.
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10% to 20% of patients are asymptomatic.

Referral

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Physical medicine and rehabilitation specialists can help with care coordination.
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Orthotist/prosthetist for orthotics or braces.
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Orthopedic consultation for surgical treatment of deformity.
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Genetic counseling and family planning.

Pearls & Considerations

Comments

Patient information on CMT disease is available from the Muscular Dystrophy Association, 3300 East Sunrise Drive, Tucson, AZ 85718; (520) 529-2000.

Ferri – Charcot-Marie-Tooth Disease