DETECTION OF THE MACHADO-JOSEPH DISEASE SPINOCEREBELLAR ATAXIA 3 TRINUCLEOTIDE REPEAT EXPANSION IN FAMILIES WITH AUTOSOMAL-DOMINANT MOTOR DISORDERS, INCLUDING THE DREW FAMILY OF WALWORTH

Affected members of 63 families with a variety of autosomal dominant l ate onset cerebellar ataxias (ADCA), and 29 patients with similar phen otypes but no affected relatives, were investigated for the trinucleot ide (CAG) repeat expansion described in Japanese families with Machado -Joseph disease (MJD). This disorder had previously been shown to map To the region of chromosome 14 which also contains a locus causing ADC A in French families, spinocerebellar ataxia 3 (SCA3). The MJD/SCA3 mu tation was identified in nine families with ADCA type I, and a further family in which affected members had parkinsonism, peripheral neuropa thy, dystonia, and spasticity, but little evidence of cerebellar disea se. Only one of the 10 families was British (the Drew family of Walwor th); the others originated from India, Jamaica, Ghana, Brazil and Fran ce. There was no single clinical feature which distinguished patients with the MJD/SCA3 mutation from those with the CAG expansion on chromo some 6 (SCA1) or ADCA type I families with no known mutation. The CAG repeat length ranged from 13-41 copies on normal chromosomes and 62-80 copies on affected chromosomes. There was a significant inverse corre lation between age of onset of symptoms and repeat length, but no sign ificant effect of parental sex on repeat length or age of onset in off spring. DNA analysis for the MJD/SCA3 mutation is useful for diagnosis in patients with familial ataxic or extrapyramidal syndromes, and wil l aid genetic counselling in these disorders.