Abstract
Spinocerebellar ataxia type 2 (SCA2) is caused by a CAG trinucleotide repeat expansion within the coding region of the ataxin-2 gene. Affected individuals typically have between 34 and 57 CAG repeats.
Signs of the disorder generally begin in adulthood and include progressive ataxia, dysarthria, tremor, hyporeflexia, and slow saccades. As with other trinucleotide repeat disorders, SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at onset of clinically detectable disease, with neonatal cases of SCA2 being reported in individuals harboring over 200 CAG repeats.
However, a wide range of age at onset is typically observed, especially in individuals with <40 CAG repeats. CAG repeat number alone explains -25-80% of the variability.
In this paper, we hypothesize that the level of mutant ataxin-2 protein in affected cells contributes to these differences. One of the mechanisms that might influence this protein levels is de novo DNA methylation, which would specifically target the allete with the expanded CAG repeat leading to transcriptional silencing.
Consequently, the symptoms of SCA2 would occur later in the patient's life history. Our postulations, as well as those previously reported to account for the phenotype of SCA2, are discussed.