Sisters homozygous for the spinocerebellar ataxia type 6 (SCA6)/CACNA1A gene associated with different clinical phenotypes

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by a CAG repeat expansion in the CACNA1A gene. The neurodegeneration that o ccurs in CAG repeat diseases is considered to share a common mechanism that may result in the gain of a toxic function related to the expanded polyglu tamine tracts. However, the phenotypic expression in homozygotes for CAG re peat diseases has been controversial, and is not clearly related to a gain of functional mechanism. We identified a Japanese family with two sisters w ho were homozygous for the SCA6 with identical CAG repeat expansion (25/ 25 ). They showed an earlier age of onset (27 years in both) than their father (44 years), a heterozygote with an expanded allele showing the same CAG re peat length as the homozygotes (25/14). Interestingly, the two sisters show ed differences in disease progression and severity, although the age of ons et and CAG repeat length were identical. These findings strongly suggest th at the gene dosage influences the age of onset, but other unknown factors a re also important in the phenotypic expression of homozygous SCA6.