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.

Clinical Manifestations

The presentation is in late childhood or adolescence, with recurrent episodes of burning pain and paresthesias of the feet and lower legs so severe that patients are unable to walk. These episodes are often precipitated by fever or by physical activity. Objective sensory and motor deficits are not demonstrated on neurologic examination, and reflexes are preserved. Characteristic skin lesions are seen in the perineal region, scrotum, buttocks, and periumbilical zone as flat or raised red-black telangiectases known as angiokeratoma corporis diffusum. Hypohidrosis may be present. Corneal opacities, cataracts, and necrosis of the femoral heads are inconstant features. Tortuosity of retinal vessels and of the vertebral and basilar arteries can occur. The disease is progressive. Hypertension and renal failure are usually delayed until early adult life. Recurrent strokes result from vascular wall involvement. Death often occurs in the 5th decade owing to cerebral infarction or renal insufficiency, but a significant morbidity already occurs in childhood despite the absence of major organ failure. Heterozygous female carriers may be asymptomatic or, rarely, are as affected as males; corneal opacities involve 70-80%, though cataracts are rare.

Laboratory Findings

Motor and sensory nerve conduction velocities are normal to only mildly slow, showing preservation of large myelinated nerve fibers. CSF protein is normal. Proteinuria is present early in the course.

Pathologic features are usually first detected in skin or sural nerve biopsy specimens. Crystalline glycosphingolipids appear as zebra bodies in lysosomes of endothelial cells, in smooth myocytes of arterioles, and in Schwann cells, best demonstrated by electron microscopy. Nerves show a selective loss of small myelinated fibers and relative preservation of large and medium-sized axons, contrasting to most axonal neuropathies in which large myelinated fibers are most involved.

Assay for the deficient enzyme, α-galactosidase-A, may be performed from skin fibroblasts, leukocytes, and other tissues. This test permits detection of the female carrier state and provides a reliable means of prenatal diagnosis.

Treatment

(See Chapter 80.4 for specific therapy of Fabry disease, including enzyme replacement.)

Medical therapy of painful neuropathies includes management of the initiating disease and therapy directed to the neuropathic pain independent of etiology. Pain may be burning or associated with paresthesias, hyperalgesia (abnormal response to noxious stimuli), or allodynia (induced by non-noxious stimuli; Chapter 71). Neuropathic pain is often successfully managed by tricyclic antidepressants; selective serotonin reuptake inhibitors are less effective. Anticonvulsants (carbamazepine, phenytoin, gabapentin, lamotrigine) are effective, as are narcotic and non-narcotic analgesics. Enzyme replacement therapy has improved the short and long term prognosis.