Hereditary Motor-Sensory Neuropathies

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Chapter 605 Hereditary Motor-Sensory Neuropathies

The hereditary motor-sensory neuropathies (HMSNs) are a group of progressive diseases of peripheral nerves. Motor components generally dominate the clinical picture, but sensory and autonomic involvement is expressed later.

605.1 Peroneal Muscular Atrophy (Charcot-Marie-Tooth Disease; HMSN Type I)

Harvey B. Sarnat

Charcot-Marie-Tooth disease is the most common genetically determined neuropathy and has an overall prevalence of 3.8/100,000. It is transmitted as an autosomal dominant trait with 83% expressivity; the 17p11.2 locus is the site of the abnormal gene. Autosomal recessive transmission also is described but is rarer. The gene product is peripheral myelin protein 22 (PMP22). A much rarer X-linked HMSN type I results from a defect at the Xq13.l locus, causing mutations in the gap junction protein connexin-32. Other forms have been reported (Table 605-1).

Clinical Manifestations

Most patients are asymptomatic until late childhood or early adolescence, but young children sometimes manifest gait disturbance as early as the 2nd year of life. The peroneal and tibial nerves are the earliest and most severely affected. Children with the disorder are often described as being clumsy, falling easily, or tripping over their own feet. The onset of symptoms may be delayed until after the 5th decade.

Muscles of the anterior compartment of the lower legs become wasted, and the legs have a characteristic stork-like contour. The muscular atrophy is accompanied by progressive weakness of dorsiflexion of the ankle and eventual footdrop. The process is bilateral but may be slightly asymmetric. Pes cavus deformities invariably develop due to denervation of intrinsic foot muscles, further destabilizing the gait. Atrophy of muscles of the forearms and hands is usually not as severe as that of the lower extremities, but in advanced cases contractures of the wrists and fingers produce a claw hand. Proximal muscle weakness is a late manifestation and is usually mild. Axial muscles are not involved.

The disease is slowly progressive throughout life, but patients occasionally show accelerated deterioration of function over a few years. Most patients remain ambulatory and have normal longevity, although orthotic appliances are required to stabilize the ankles.

Sensory involvement mainly affects large myelinated nerve fibers that convey proprioceptive information and vibratory sense, but the threshold for pain and temperature can also increase. Some children complain of tingling or burning sensations of the feet, but pain is rare. Because the muscle mass is reduced, the nerves are more vulnerable to trauma or compression. Autonomic manifestations may be expressed as poor vasomotor control with blotching or pallor of the skin of the feet and inappropriately cold feet.

Nerves often become palpably enlarged. Tendon stretch reflexes are lost distally. Cranial nerves are not affected. Sphincter control remains well preserved. Autonomic neuropathy does not affect the heart, gastrointestinal tract, or bladder. Intelligence is normal. A unique point mutation in PMP22 causes progressive auditory nerve deafness in addition, but this is usually later in onset than the peripheral neuropathy.

Davidenkow syndrome is a variant of HMSN type I with a scapuloperoneal distribution.