Neurological phenotypes in spinocerebellar ataxia type 2: Role of mitochondrial polymorphism A10398G and other risk factors

Abstract Background Spinocerebellar ataxia type 2 (SCA2) is due to a CAG expansion (CAGexp) at ATXN2 . SCA2 presents great clinical variability, alongside characteristic ataxia with saccadic slowness. Aims To study parkinsonism, dementia, dystonia, and amyotrophy as subphenotypes of SCA2, and to explore the effect of CAG repeats at different loci and of mitochondrial polymorphism A10398G as modifiers of phenotype. Methods Symptomatic subjects were classified by presence/absence of neurological signs mentioned above; SARA and NESSCA scores were obtained. CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7 and RAI1 , and polymorphism A10398G at mtDNA were established. Group characteristics were compared, with a p  Results Forty-eight SCA2 individuals were included. Age at onset, CAGexp, and disease duration explained 53% and 43% of SARA and NESSCA variations, respectively. CAGexp of subjects with and without parkinsonism were different (medians of 42 and 39 repeats) as well as of subjects with and without dystonia (44 and 40 repeats). Amyotrophy was not significantly related to any variable under study. Concerning polymorphism A10398G, 83% of subjects with and 34% of those without cognitive decline carried 10398G at (p = 0.003). Discussion Treating the four phenotypic subgroups as outcomes was a valid strategy to identify modifiers of disease. Among correlations found, some confirmed previous reports, such as that between dystonia and CAGexp. Of note was the association between cognitive decline and the variant G at mitochondrial polymorphism A10398G, a variant formerly related to earlier ages at onset in SCA2.