Joseph's disease: an autosomal dominant neurological disease in the Portuguese of the United States and the Azores Islands.

Our objective has been to trace Joseph's disease to its geographic origins and to determine the spectrum of clinical manifestations. This goal we have achieved by documenting type I and II disease within the Joseph and Sousa families. The major neuropathologic findings are a progressive neuronal loss involving the striatum, nigra, dentate nucleus of the cerebellum, and lower motor neurons in the brainstem and spinal cord. The homozygote form of the disease produces type I disease with onset in early childhood of progressive dystonia, athetosis, and spasticity. Type I disease tends to have its onset by age 25 years in heterozygotes and lasts about 15 years on the average. Type II disease, which we consider the result of a single dose of the mutant gene, usually begins somewhat later and runs its course over a 20-year period. Type III disease documented in the Thomas family is the most benign. Its onset is often in the fifth decade, and it progresses slowly into the eighth decade. Patients may benefit from antiparkinson medication including dihydroxyphenylalanine and anticholinergic agents (e.g., amantadine). A molecular marker for the disease is being sought actively, and several interesting patterns have already been documented by means of patient fibroblast cultures and two-dimensional acrylamide gel protein separations. The mutant gene is clearly outside the HLA complex but may be linked to it. The only biochemical change noted thus far is a reduced CSF level of HVA that probably reflects the loss of dopamine-synthesizing neurons in the substantia nigra and is thus a secondary effect of disease. Although the disease is a very old one which we can trace back to the early 19th century on the island of Flores, it may be recurring de novo by new gene mutations at an unstable gene locus in a genetically vulnerable population. Now that the spectrum of clinical expression has been identified and the mode of inheritance established as an autosomal dominant wherever the disease has been found, it is believed that its true incidence will become more evident by virtue of better detection and that the true incidence will actually increase because of increased assimilation of affected persons into other ethnic groups.