The Siberian kindred with autosomal dominant cerebellar ataxia type 1 includes 1484 individuals, 225 affected and 656 at risk. The expanded allele in each of 78 examined patients contained a stretch of 39 to 72 uninterrupted CAG repeats in the SCA1 gene on chromosome 6. The normal allele had 25 to 37 trinucleotide repeats. The number of CAG repeats inversely correlated with the age of disease onset and the duration of illness. Progressive cerebellar deficiency was expressed in all patients, independently of the repeat number; the associated symptoms, diffuse skeletal muscle atrophy, dysphagia, tongue atrophy with fasciculation and ophthalmoparesis, had a significantly higher prevalence among patients with the number of CAG repeats 52 and over. Two symptomatic individuals had CAG repeat expansion on both chromosomes. A CAG trinucleotide repeat expansion was also identified in the coding region of the Machado-Joseph disease gene on chr 14q in nine American families of Portuguese, German, Irish and Dutch-African ancestry. All 25 affected members were heterozygous for an expanded allele containing 67 to 83 CAG repeats whereas the normal allele had 6 to 33 repeats. We have identified two novel mutations in the phosphofructokinase muscle subunit gene associated with glycogenosis type VII (Tarui's disease) in three patients from an Ashkenazi Jewish family: a nonsense mutation at codon 95 and 252-nucleotide insertion totally homologous to the structure of the 10th intron. The resulting truncated protein preserves some enzyme activity and is able to function at 33% of the normal level. Opticopharyngeal muscular atrophy is being studied in a large family originating from Bukhara, Central Asia. This disease in another large family has previously been linked to a locus on chromosome 14q; our data excluded linkage of the Bukhara family to this locus suggesting genetic heterogeneity. In hereditary inclusion-body myopathy, the deposits in the vacuolated muscle fibers were immunocytochemically identified as Abeta amyloid of Alzheimer's type or admixture of Abeta and prion protein (PrP) amyloids. Complete sequencing of the beta-amyloid portion of the APP gene in four patients and PRNP coding region in two affected individuals did not reveal any abnormalities. A genome-wide search is being performed with three large American families with essential tremor, with the use of highly polymorphic minisatellite markers.
