Mutation in <i>GM2A</i> Leads to a Progressive Chorea-dementia Syndrome

Abstract

<strong>Background:</strong> The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new diseaseassociated genes and variant phenotypes associated with known genes. <strong>Methods:</strong> We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing. <strong>Results:</strong> We identified a homozygous missense mutation in <em>GM2A</em> within a prominent block of homozygosity. This mutation is predicted to impair protein function. <strong>Discussion:</strong> Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described <em>GM2A</em> patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.