A closely related disease, also with familial hypobetalipoproteinemia, was described by van Buchem and coworkers. It, too, is associated with malabsorption syndrome, ill-defined weakness, ataxia, dysesthesia of the legs, and Babinski signs. There is no sensory loss.
This is a rare, familial, small-fiber neuropathy of which we have seen a few cases, inherited as an autosomal recessive trait. It is named for the island off the Virginia coast where the first-described patients resided. The mutation eliminates the function of the adenosine triphosphate (ATP)-cassette transporter protein, ABC1. It results in a deficiency of high-density lipoprotein, extremely low serum cholesterol, and high triglyceride concentrations in the serum. Perhaps on the basis of these abnormalities, the patients are disposed to early and severe atherosclerosis. The presence of enlarged, yellow-orange (cholesterol-laden) tonsils is said to be a frequent manifestation (of course, previous tonsillectomies obviate this sign). About half of the reported cases have had neuropathic symptoms, taking the form of an asymmetrical sensorimotor neuropathy that fluctuates in severity.
The sensory loss is predominantly for pain and temperature and extends over the entire body; at times it is limited to the face and upper extremities, simulating syringomyelia (“pseudosyringomyelia”). Tactile and proprioceptive sensory modalities tend to be preserved. The polyneuropathy may come in attacks—that is to say, it simulates a recurrent process. Muscular weakness, if present, affects either the lower or upper extremities or both, particularly the hand muscles, which may undergo atrophy and show denervation by EMG. In a small number of patients there has been facial diplegia out of proportion to weakness elsewhere. In one of our patients, the pain and temperature loss was restricted to the head, neck, and arms. Tendon reflexes are often lost or diminished. Transient ptosis and diplopia have been reported. Nerve conduction is slowed.
Fat-laden macrophages are present in the bone marrow and elsewhere. No complete pathologic studies are available. There is no known treatment but dietary measures to reduce triglycerides may help, particularly in preventing atherosclerosis but the influence on the neuropathy is uncertain.
Fabry Disease (Anderson-Fabry Disease, GLA Mutation) (See Also Chap. 36)
The genetic and metabolic aspects of this sex-linked disorder caused by deficiency of alpha-galactosidase A were considered with the inherited metabolic diseases. Here we offer some additional remarks about the painful neuropathic component. It bears commenting that 10 percent of heterozygous women display neuropathic symptoms, but usually of later onset and lesser degree than in males.
The pain, which is usually the initial symptom in childhood and adolescence, often has a burning quality or occurs in brief lancinating jabs, mostly in the fingers and toes, and may be accompanied by paresthesias of the palms and soles. Changes in environmental temperature and exercise may induce pain in “crises,” an identifying feature. These abnormalities are a result of the accumulation of glycolipid (ceramide trihexoside) in peripheral nerves, both perineurally and intraneurally, as well as in cells of the spinal ganglia and the anterior and intermediolateral horns of the spinal cord. Ohnishi and Dyck demonstrated a preferential loss of small myelinated and unmyelinated fibers and small neurons of dorsal root ganglia, and by autonomic changes in other cases. Involvement of the sensory ganglia and the associated degenerative changes in the afferent fibers are thought to be the likely cause of the thermally induced painful sensory phenomena (Kahn 1973).