Clinical and molecular analysis of 11 Sicilian SCA2 families: influence of gender on age at onset

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Abstract
Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of slowly progressive neurodegenerative disorders characterized by gait and stance ataxia, dysarthria and other symptoms of nervous system involvement. ADCA type I is the commonest form and is genetically heterogeneous; several loci have been identified. Spinocerebellar ataxia type 2 (SCA2) has been mapped to chromosome 12, with expanded cytosine‐adenine‐guanine (CAG) repeats being identified as the mutational cause of the disease. We investigated 15 families, all originating from mid‐eastern Sicily, with ADCA type I; molecular studies performed in 12 families showed the SCA2 mutation to be present in 11 of them (91.6%) ‐ the highest occurrence so far reported in the literature. The CAG repeat of the affected alleles varied between 34 and 44 repeats. Age at onset and repeat length revealed an inverse correlation. Mean age at onset was 37.32 ± 16.74 years, and occurred earlier in males than in females. There were no differences in mean CAG repeat units between the sexes. However, a higher instability of CAG repeats was observed for paternal transmission than for maternal transmission. Age at onset and anticipation were not related to parental transmission. Our data suggest that in SCA2 an unknown sexlinked factor may play a role in the modulation of toxic effects of the polyglutamine tract.