SPINOCEREBELLAR ATAXIA TYPE-6 - GAZE-EVOKED AND VERTICAL NYSTAGMUS, PURKINJE-CELL DEGENERATION, AND VARIABLE AGE-OF-ONSET

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansi ons of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromos ome 19p13, which encodes the alpha 1 subunit of a P/Q-type voltage-gat ed calcium channel. We describe clinical, genetic, neuroimaging, neuro pathological, and quantitative oculomotor studies in four kindreds wit h SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 rep eat units. It is noteworthy that the age of onset of ataxia ranged fro m 24 to 63 years among all affected individuals, despite the uniform r epeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocu lar motor and vestibular abnormalities, including horizontal and verti cal nystagmus and an abnormal vestibule-ocular reflex. These studies i dentify a distinct phenotype associated with this newly recognized for m of dominant SCA.