Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expan sion alleles can have highly variable disease onset indicating that other factor s also influence AO. We examined AO in 148 individuals in 57 sibships from the S CA2 founder population in Cuba. The mutant CAG repeat allele explained 57%of AO variance. To estimate heritability of the residual variance after correction fo r SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55%of the residual AO vari ance was familial. To test candidate modifier alleles in this population, we sel ected 64 unrelated individuals from a set of 394 individuals who were highly dis cordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with pre mature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeat s in the CACNA1A gene were associated with disease onset earlier than expected b ased on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A var iation explained 5.8%of the residual variation in AO. The CACNA1A calcium chann el subunit represents an excellent candidate as a modifier of disease in SCA2. I t is highly expressed in Purkinje cells (PCs) and is essential for the generatio n of the P/Q current and the complex spike in PCs. In contrast to other polyQ pr oteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. F urthermore, small pathologic expansions of the polyQ domain in the CACNA1A prote in lead to PC degeneration in SCA6. Future studies are needed to determine wheth er the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons. Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expan sion alleles can have highly variable disease that indicating that other factor s also influence AO. We examined AO in 148 individuals in 57 sibships from the CA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance To estimate heritability of the residual variance after correction fo r SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO vari ance was familial. To test candidate modifier alleles in this population, we sel ected 64 unrelated individuals from a set of 394 individuals who were highly dis cordant for AO after correction for S CA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with pre mature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeat s in the CACNA1A gene were associated with disease earlier onset than expected b ased on SCA2 CAG repeat size using non-parametric tests for alleles (P <0.04) and genotypes (P <0.023) after correction for multiple comparisons. CACNA1A var iation explained 5.8% of the residual variation in AO. The CACNA1A calcium chann el subunit represents an excellent candidate as a modifier of disease in SCA2. I t is highly expressed in Purkinje cells (PCs) and is essential for the generatio n of the P / Q current and the complex spike in PCs. In contrast to other polyQ pr oteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. F urthermore, small pathologic expansions of the polyQ domain in the CACNA1A prote in lead to PC degeneration in SCA6.rmine wheth er the modifier effect of CACNA1A to neuronal dysfunction or cell death of Purkinje neurons.