PROGRESSIVE ATAXIA DUE TO A MISSENSE MUTATION IN A CALCIUM-CHANNEL GENE

We describe a family with severe progressive cerebellar ataxia involvi ng the trunk, the extremities, and speech. The proband, who has promin ent atrophy of the cerebellum, shown by magnetic resonance imaging, wa s confined to a wheelchair at the age of 44 years. Two sons have episo des of vertigo and ataxia that are not responsive to acetazolamide. Qu antitative eye-movement testing showed a consistent pattern of abnorma lities localizing to the cerebellum. Genotyping suggested linkage to c hromosome 19p, and SSCP showed an aberrant migrating fragment in exon 6 of the calcium-channel gene CACNA1A, which cosegregated with the dis ease. Sequencing of exon 6 identified a G --> A transposition in one a llele, at nucleotide 1152, resulting in a predicted glycine-to-arginin e substitution at codon 293. The CAG-repeat expansion associated with spinocerebellar ataxia 6 was not present in any family members. This f amily is unique in having a non-CAG-repeat mutation that leads to seve re progressive ataxia. Since a great deal is known about the function of calcium channels, we speculate on how this missense mutation leads to the combination of clinical symptoms and signs.