G.P.92 Study of an autosomal recessive spinocerebellar ataxia with peripheral neuropathy

Abstract The autosomal recessive spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders associated with 10 disease genes and seven other loci. Because of the genetic and phenotypic heterogeneity of this disease, a large percentage of cases go without a genetic diagnosis. In the family under investigation, two out of eight siblings are affected, and the parents are second cousins, suggesting a recessive disease. The two affected brothers presented at 55 and 54 years respectively with weakness about the ankles, poor balance and chronic cough. There were cerebellar signs with saccadic interruption of eye movements and a wide-based gait, and later on dysarthria. Creatine kinase was elevated, to between 580 and 1020 ( N < 195). Nerve conduction studies showed a severe sensorimotor peripheral neuropathy and muscle biopsy showed numerous atrophic fibres and group atrophy, in keeping with a neurogenic cause. Electron microscopy additionally showed subsarcolemmal accumulation of pleomorphic mitochondria with large electron dense inclusions. MRI of the head showed progressive atrophy of the cerebellum, principally of the vermis, and thinning of the brainstem. No cause for the cough has been found. This combination of pathologies has not previously not been described in the literature, thus suggesting that this is a novel phenotype of recessive spinocerebellar ataxia. We have combined SNP-based linkage analysis with whole exome capture and next generation sequencing to attempt to identify the causative mutation in this family. Linkage exclusion analysis combined with whole exome sequencing has eliminated all known autosomal recessive spinocerebellar ataxia disease genes, indicating that a novel disease gene may be the cause of disease in this family.