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)
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.
Laboratory Findings and Diagnosis
Motor and sensory nerve conduction velocities are greatly reduced, sometimes as slow as 20% of normal conduction time. In new cases without a family history, both parents should be examined, and nerve conduction studies should be performed.
Electromyography (EMG) and muscle biopsy are not usually required for diagnosis, but they show evidence of many cycles of denervation and reinnervation. Serum creatine kinase level is normal. Cerebrospinal fluid (CSF) protein may be elevated, but no cells appear in the CSF.
Sural nerve biopsy is diagnostic. Large- and medium-sized myelinated fibers are reduced in number, collagen is increased, and characteristic onion bulb formations of proliferated Schwann cell cytoplasm surround axons. This pathologic finding is called interstitial hypertrophic neuropathy. Extensive segmental demyelination and remyelination also occur.
The definitive molecular genetic diagnosis may be made in blood.
Treatment
Stabilization of the ankles is a primary concern. In early stages, stiff boots that extend to the mid-calf often suffice, particularly when patients walk on uneven surfaces such as ice and snow or stones. As the dorsiflexors of the ankles weaken further, lightweight plastic splints may be custom made to extend beneath the foot and around the back of the ankle. They are worn inside the socks and are not visible, reducing self-consciousness. External short-leg braces may be required when footdrop becomes complete. Surgical fusion of the ankle may be considered in some cases.
The leg should be protected from traumatic injury. In advanced cases, compression neuropathy during sleep may be prevented by placing soft pillows beneath or between the lower legs. Burning paresthesias of the feet are not common but are often abolished by phenytoin or carbamazepine. No medical treatment is available to arrest or slow the progression.
605.2 Peroneal Muscular Atrophy (Axonal Type)
Peroneal muscular atrophy is clinically similar to HMSN type I, but the rate of progression is slower and the disability is less. EMG shows denervation of muscle. Sural nerve biopsy reveals axonal degeneration rather than the demyelination and whorls of Schwann cell processes typical in type I. The locus is on chromosome 1 at 1p35-p36; this is a different disease than HMSN type I, although both are transmitted as autosomal dominant traits. An autosomal recessive infantile motor axonal neuropathy can closely mimic infantile spinal muscular atrophy.
605.3 Déjerine-Sottas Disease (HMSN Type III)
Déjerine-Sottas disease is an interstitial hypertrophic neuropathy of autosomal dominant transmission. It is similar to HMSN type I but is more severe. Symptoms develop in early infancy and are rapidly progressive. Pupillary abnormalities, such as lack of reaction to light and Argyll Robertson pupil, are common. Kyphoscoliosis and pes cavus deformities complicate about 35% of cases. Nerves become palpably enlarged at an early age.
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