Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis

We studied a large kindred with a chronic progressive neurologic disorder affecting at least 10 men and 11 women in four generations in a pattern compatible with autosomal dominant inheritance. In 20 of the affected subjects, evaluated before the availability of computerized tomography and without regard to family history, the diagnosis was multiple sclerosis. Symptoms of the neurologic disorder begin in the fourth and fifth decades and include cerebellar, pyramidal, and autonomic abnormalities. The autonomic symptoms, which involve bowel and bladder regulation and orthostatic hypotension, may be the earliest changes but are frequently disregarded. Survival for 20 years after onset is common. The CT scan is striking and shows a symmetrical decrease in white-matter density, beginning in the frontal lobes but extending to all of the centrum ovale and the cerebellar white matter. Limited pathological observation reveals gross white-matter degeneration with microscopic vacuolation, preservation of U fibers and cortical structures, and no inflammatory changes or reactive gliosis. Because of its hereditary basis, the disorder should be susceptible to genetic definition and ultimately to treatment or prevention.