Genetic and clinical analysis of SCA8 repeat expansion

Spinocerebellar ataxia type 8 is the first dominant form of ataxia caused by a CTG trinucleotide repeat expansion in the untranslated region of the disease gene. This disorder, clinically characterized by pure cerebellar ataxia with slow disease progression, shows maternal anticipation in contrast to the majority of dominant SCAs showing paternal anticipation. Normal alleles have a repeat size varying from 16 to 91 combined CTG/CTA repeats, whereas SCA8 patients carry expanded alleles with 107-127 pure CTGs. However, possible pathogenic combined repeats of 92-250 (CTA)/(CTG) repeats were reported in ataxic patients since the original report. In addition, recent collaborative studies, using large groups of patients and controls reported nonspecific SCA8 pathogenic expansions in healthy subjects, and in patients with various neurological and psychiatric disorders, suggesting that CTG expansions linked to SCA8 may represent rare polymorphisms. In order to better define the molecular features of these expansions, we genotyped for SCA8 114 ataxic patients, including 50 cases of autosomal dominant cerebellar ataxia, 15 with suspected autosomal recessive cerebellar ataxia, and 49 sporadic cases, 115 healthy controls, 46 healthy centenarians, 64 schizophrenic patients, and 61 patients with a familial history of bipolar affective disorders. SCA8 repeat expansions in the pathogenic range were identified in two families with autosomal recessive pure cerebellar ataxia, in one ataxic patient with vitamin E deficiency with an unknown gene defect, and in one sporadic patient with suspected gluten ataxia. Repeats in the normal range were observed in the remaining population. These results extend the phenotypic range of expanded alleles, suggesting that pathogenic expansions in the SCA8 locus may cause ataxia. A possible epistatic effect of this gene on susceptibility to malabsorption disturbances leading to ataxia could also be speculated.