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Hereditary Neuropathies

by Michael Rubin, MDCM

Hereditary neuropathies include a variety of congenital degenerative peripheral neuropathies.

Hereditary neuropathies are classified as

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 (I, II, and III); all begin in childhood. Some less common types begin at birth and result in greater disability.

Types I and II (varieties of Charcot-Marie-Tooth disease, also called peroneal muscular atrophy) are the most common; they are usually autosomal dominant disorders but can be 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. These disorders 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 type I 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. Type II evolves more 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.

Type III (hypertrophic interstitial neuropathy, Dejerine-Sottas disease), a rare autosomal recessive disorder, 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. Five 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

The characteristic distribution of motor weakness, foot deformities, and family history suggests the diagnosis, which should be confirmed by electrodiagnostic testing. Genetic analysis is available, but there are no specific treatments.

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.

Hereditary Motor Neuropathy With Liability to Pressure Palsies (HNPP)

In hereditary motor neuropathy with liability to pressure palsies (HNPP), nerves become increasingly sensitive to pressure and stretch.

In HNPP (tomaculous neuropathy), nerves lose their myelin sheath and do not conduct nerve impulses normally. Inheritance is usually autosomal dominant. In 80%, the cause is loss of one copy of peripheral myelin protein-22 gene ( PMP22 ), located on the short arm of chromosome 17. Two copies of the gene are needed for normal function. Incidence of HNPP is estimated to be 2 to 5/100,000.

Usually, symptoms start during adolescence or young adulthood, but they may start at any age. Peroneal nerve palsy with footdrop, ulnar nerve palsy, and carpal tunnel syndrome commonly develop. The pressure palsies can be mild or severe and last from minutes to months. Numbness and weakness occur in affected areas. After an episode, about half of affected people completely recover, and symptoms are mild in most of the rest.

Diagnosis

HNPP should be suspected in patients with any of the following:

  • Recurrent compression mononeuropathies

  • Multiple mononeuropathy of unknown origin

  • Symptoms suggesting recurrent demyelinating polyneuropathy

  • A family history of carpal tunnel syndrome

Electrodiagnostic testing and genetic testing aid in diagnosis; rarely, biopsy is required.

Treatment

  • Supportive care

Treatment involves avoiding or modifying activities that cause symptoms. Wrist splints and elbow pads can reduce pressure, prevent reinjury, and allow the nerve to repair the myelin over time. Surgery is rarely indicated.

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