MACHADO-JOSEPH-DISEASE - CLINICAL, MOLECULAR, AND METABOLIC CHARACTERIZATION IN CHINESE KINDREDS

Machado-Joseph disease, an autosomal dominant multisystem motor degene ration, has been described mainly in people of Portuguese descent. Our report documents the presence of Machado-Joseph disease in the Chines e population, based on the specific molecular marker of a CAG repeat a rray in the 3' end of the MJD gene. We screened 21 Chinese families wi th dominant spinocerebellar ataxia. The results showed that Machado-Jo seph disease with GAG expansion accounted for 52% of families with aut osomal dominant cerebellar ataxia in this series. The clinical charact eristics, besides the well-documented cerebellar ataxia, dysarthria, n ystagmus, corticospinal dysfunctions, a variable degree of facial musc le fasciculation, and proprioceptive loss, included loss of optokineti c nystagmus and autonomic nervous system dysfunction, The CAG repeat n umber in the MJD gene ranged from 14 to 39 among normal alleles, and f rom 63 to 81 among MJD alleles. There was a strong inverse correlation (gamma = -0.77) between number of CAG repeats and age at symptom onse t, accounting for 60% of the variance of age at onset. A strong clinic al anticipation of age at onset existed in successive generations. Mil d instabilities of expanded CAG repeat numbers during meiotic transmis sion occurred, with no significant difference according to the gender of the transmitting parent. Finally, brain metabolism in Machado-Josep h disease, studied with positron emission tomography, was characterize d by significant progressive regional hypometabolism in the occipital cortex, as well as the cerebellar hemispheres, vermis, and brainstem.