Clinical and genetic study of autosomal recessive cerebellar ataxia type 1

Objective: Define the phenotype and genotype of a cluster of families with a relatively pure cerebellar ataxia referred to as autosomal recessive cerebellar ataxia type 1 (ARCA-1). Methods: We ascertained 64 probands and affected members of 30 French-Canadian families all showing similar clinical features and originating from the same region of Quebec. After informed consent, we performed detailed clinical history, neurological examination, brain imaging, nerve conduction studies, and SYNE1 mutation detection of all available subjects. Results: Based on the cases examined, ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability, significant dysarthria, mild oculomotor abnormalities, occasional brisk reflexes in the lower extremities, normal nerve conduction studies, and diffuse cerebellar atrophy on imaging. We identified a total of seven mutations in our population, thereby providing evidence of genotypic heterogeneity. Patients with different mutations did not show significant phenotypic heterogeneity. Interpretation: We identified a cluster of French-Canadian families with a new recessive ataxia of relatively pure cerebellar type caused by mutations in SYNE1 The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans. We expect that this disease will be a common cause of middle-age-onset recessive ataxia worldwide.