Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy

Senataxin recently was identified as the mutated gene in ataxia-oculomotor apraxia 2, which is characterized by ataxia, oculomotor apraxia, and increased α-fetoprotein levels. In this study, we evaluated 24 ataxic patients from 10 French-Canadian families. All cases have a homogeneous phenotype consisting of a progressive ataxia appearing between 2 and 20 (mean age, 14.8) years of age with associated dysarthria, saccadic ocular pursuit, distal amyotrophy, sensory and motor neuropathy, and increased α-fetoprotein levels but absence of oculomotor apraxia. Linkage disequilibrium was observed with markers in the ataxia-oculomotor apraxia 2 locus on chromosome 9q34. We have identified four mutations in senataxin in the French-Canadian population including two novel missense mutations: the 5927TG mutation changes the leucine encoded by codon 1976 to an arginine in the helicase domain (L1976R), and the 193GA mutation changes a glutamic acid encoded by codon 65 into a lysine in the N-terminal domain of the protein (E65K). The common L1976R mutation is shared by 17 of 20 (85%) carrier chromosomes. The study of this large French-Canadian cohort better defines the phenotype of this ataxia and presents two novel mutations in senataxin including the more common founder mutation in the French-Canadian population. Ann Neurol 2005;57:408–414