G.P.93 Study of a novel autosomal dominant spinocerebellar ataxia

Abstract

Abstract The spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. There are currently 18 known disease genes and nine other loci that have been associated with autosomal dominant spinocerebellar ataxia. Because of this genetic heterogeneity, a large number of cases still go without a genetic diagnosis. The family under investigation is a four-generation family of Anglo-Saxon lineage, with eight known affected members. The phenotype is of an autosomal dominant spinocerebellar ataxia, with evidence of anticipation. The initial symptom is gait ataxia, followed within 5 years by slurring dysarthria, saccadic interruption of eye movements, intention tremor, and clumsy hand movements. There is evidence of long tract involvement with increased deep tendon reflexes in the legs and urinary urgency. There is progression of all the symptoms, with the second generation requiring a wheelchair by 70 years, and the third generation by 50 years. Progressive atrophy of the cerebellum, brain stem and cerebellar peduncles develops on MRI. All other investigations were within normal limits. Molecular testing for trinucleotide repeat expansions for SCA 1, 2, 3, 6, 7, 8 and 17 was negative. We then used SNP-based linkage analysis to attempt to identify the causative locus in the family. SNP linkage analysis excluded all known autosomal dominant spinocerebellar ataxia disease genes except for SCA8 (already excluded) and (SCA10). SCA10 has not as yet been excluded. However, mutations in this gene have only been reported in families of South American or Mexican descent, and the phenotype is usually complicated with seizures and mood disorders, unlike our family. The SCA 19/22, 21 and 29 loci were not excluded. Thus, the disease in our family is either caused by a novel disease gene, or it is the first SCA10 family outside of South America and Mexico to be described.