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Hereditary Neuropathies

By

Michael Rubin

, MDCM,

  • Attending Neurologist and Director, Neuromuscular Service and EMG Laboratory
  • New York Presbyterian Hospital-Cornell Medical Center

Last full review/revision Dec 2020| Content last modified Dec 2020
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Hereditary neuropathies include a variety of congenital degenerative peripheral neuropathies (eg, Charcot-Marie-Tooth disease).

Hereditary neuropathies are classified as

  • Motor and sensory

  • Sensory and autonomic

Hereditary neuropathies may be primary or secondary to other hereditary disorders, including Refsum disease, porphyria, and Fabry disease.

Motor and sensory neuropathies

There are 3 main types (CMT1, CMT2, and CMT3) of motor and sensory neuropathies; all begin in childhood. Some less common types begin at birth and result in greater disability.

CMT1 and CMT2 (varieties of Charcot-Marie-Tooth disease, also called peroneal muscular atrophy) are the most common; they are usually autosomal dominant disorders but can be recessive or X-linked. Type I results from a duplication (extra copy) of the peripheral myelin protein-22 gene (PMP22), located on the short arm of chromosome 17; it accounts for 70 to 80% of CMT1 cases.

CMT1 and CMT2 are characterized by weakness and atrophy, primarily in peroneal and distal leg muscles. Patients often have a family history of neuropathy. Natural history varies: Some patients are asymptomatic and have only slowed conduction velocities (detected on nerve conduction studies); others are more severely affected.

Patients with CMT1 may present in middle childhood with footdrop and slowly progressive distal muscle atrophy, causing stork leg deformity. Intrinsic muscle wasting in the hands begins later. Vibration, pain, and temperature sensation decreases in a stocking-glove pattern. Deep tendon reflexes are absent. High pedal arches or hammertoes may be the only signs in family members who are carriers. Nerve conduction velocities are slow, and distal latencies are prolonged. Segmental demyelination and remyelination occur. Enlarged peripheral nerves may be palpated. The disease progresses slowly and does not affect life span. In one subtype, males have severe symptoms, and females have mild symptoms or may be unaffected.

The genetics of CMT2 is less clear. This type accounts for about 25% of all CMT cases; pathogenic mutations have been identified in only a minority of patients, perhaps 25%, with many subtypes. CMT2A is the most common CMT2 phenotype, most often due to a mutation in the gene that encodes mitochondrial fusion protein mitofusin-2 (MFN2). CMT2A is usually an autosomal dominant disorder and is axonal. It evolves slowly; weakness usually develops later in life. Patients have relatively normal nerve conduction velocities but low amplitude sensory nerve action potentials and compound muscle action potentials. Biopsies detect axonal (wallerian) degeneration.

CMT3 (also known as Dejerine-Sottas disease) is a rare congenital hypomyelinating neuropathy, which can be an autosomal dominant or a recessive disorder with mutations in several genes, including PMP22, MPZ, and EGR2 It begins in childhood with progressive weakness and sensory loss and absent deep tendon reflexes. Although initially it resembles Charcot-Marie-Tooth disease, the motor weakness progresses more quickly. Demyelination and remyelination occur, producing enlarged peripheral nerves and onion bulbs, detected by nerve biopsy.

Sensory and autonomic neuropathies

Hereditary sensory and autonomic neuropathies are rare. Seven main types have been described.

Loss of distal pain and temperature sensation is more prominent than loss of vibratory and position sense. The main complication is foot mutilation due to pain insensitivity, resulting in a high risk of infections and osteomyelitis.

Diagnosis

  • Clinical evaluation

  • Electrodiagnostic testing

The characteristic distribution of motor weakness, foot deformities, and family history suggests hereditary neuropathy, which should be confirmed by electrodiagnostic testing.

Genetic analysis is available.

Treatment

  • Supportive care

Bracing helps correct footdrop; orthopedic surgery to stabilize the foot may help.

Physical therapy (to strengthen muscles) and occupational therapy may help; vocational counseling may help prepare young patients to maintain vocational skills despite disease progression.

Key Points

  • Hereditary neuropathies may affect motor and sensory nerves, sensory nerves, sensory and autonomic nerves, or only motor nerves.

  • There are 3 main types of motor and sensory neuropathies, which vary in severity and rate of progression; nearly all begin in childhood.

  • Use braces to correct footdrop and recommend physical and occupational therapy to help patients maintain function; sometimes orthopedic surgery is needed.

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