Normal ATXN2 alleles influences on the age at onset in spinocerebellar ataxia type 2

Several studies have shown significant effects of normal alleles on the age at disease onset in Spinocerebellar ataxia type 3 (SCA3), Spinocerebellar ataxia type 1 (SCA1), and Spinocerebellar ataxia type 6 (SCA6) and Huntington’s disease (HD) patients.However, none of the studies so far conducted in SCA2 individuals has succeed to demonstrate a similar contribution of normal Ataxin-2 (ATXN2) alleles. Here, a dataset was assembled consisting of 745 affected individuals (54.23% male) belonging to 109 unique Cuban SCA2 families. All individuals were heterozygous for the ATXN2 expansion mutation with more than 31 CAG repeats at the larger allele (see Supporting Information Table S1). Normal and expanded ATXN2 alleles’ distribution and its association with the age at onset are shown in Supporting Information Figures S1 and S2. A highly significant influence of expanded and normal alleles over the age at onset was obtained, which accounted for 63.3% of the observed age at onset variability (Table 1). However, this model violates the assumptions of normality and homogeneity of variance for multiple linear regressions (Supporting Information Figures S3, S4A-C). A total of 32 cases were identified whose residues were 62 or 63 standard deviations of the mean values; these cases were excluded from the analysis. In the dataset consisting of 713 SCA2 patients, a highly significant influence of the expanded and normal alleles on the age at onset was also obtained; the interaction term was not included in the model (Table 1). This model satisfied all the assumptions for multiple linear FIG. 1. (A-C) Case 1. (A) H&E. Intraparenchymal blood vessels show thickening and hyalinization of the vessel walls, perivascular clearing, and patchy white matter rarefactions. (B) Tau1 dystrophic neurites in the neuropil and Alzheimer-type neuritic plaques and also some neurofibrillary tangles. (C) Iba11 activated microglial cells. (D-F) Case 2. (D) Hyalinized intraparenchymal vessel walls and perivascular clearing. (E) Microhemorrhages indicative of severe hypertension. (F) Diffuse white matter gliosis and increased number of Iba-1 ramified microglia throughout white matter. (G, H) Control case (no premutation). (G) Iba 1 staining shows reduced number of microglial cells with a nonactivated morphology. (H) Tau staining does not show any label. Scale bar: 50 lm. [Color figure can be viewed at wileyonlinelibrary.com]