Late-onset hereditary ataxias with dementia

Abstract

Purpose of review Late-onset genetic cerebellar ataxias are clinically heterogenous with variable phenotypes. Several of these conditions are commonly associated with dementia. Recognition of the relationship between ataxia and dementia can guide clinical genetic evaluation. Recent findings Spinocerebellar ataxias often present with variable phenotypes that may include dementia. Genomic studies have begun to identify links between incomplete penetrance and such variable phenotypes in certain hereditary ataxias. Recent studies evaluating the interaction of TBP repeat expansions and STUB1 sequence variants provide a framework to understand how genetic interactions influence disease penetrance and dementia risk in spinocerebellar ataxia types 17 and 48. Further advances in next generation sequencing methods will continue to improve diagnosis and create new insights into the expressivity of existing disorders. Summary The late-onset hereditary ataxias are a clinically heterogenous group of disorders with complex presentations that can include cognitive impairment and/or dementia. Genetic evaluation of late-onset ataxia patients with dementia follows a systemic testing approach that often utilizes repeat expansion testing followed by next-generation sequencing. Advances in bioinformatics and genomics is improving both diagnostic evaluation and establishing a basis for phenotypic variability. Whole genome sequencing will likely replace exome sequencing as a more comprehensive means of routine testing.