A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

摘要: Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated accounts for clinical presentations, making genotype-phenotype correlations major challenge the field. While polyglutamine ataxias, linked to CAG repeat expansions such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, been extensively characterized cohorts, there is need comprehensive assessment frequency phenotype more 'conventional' ataxias. After exclusion CAG/polyglutamine spinocerebellar ataxia 412 index cases dominantly inherited we aimed establish relative frequencies other genes, an approach combining panel sequencing TaqMan® polymerase chain reaction assay. We found relevant variants 59 patients (14.3%). The most frequently mutated were channel [CACNA1A (n = 16), KCND3 4), KCNC3 2) KCNA1 2)]. Deletions ITPR1 11) followed by biallelic SPG7 9). Variants AFG3L2 7) came next frequency, rarely STBN2 2), ELOVL5, FGF14, STUB1 TTBK2 1 each). Interestingly, possible risk factor detected POLG. Clinical comparisons showed that due channelopathies had significantly earlier age at onset average 24.6 years, versus 40.9 years expansion 37.8 SPG7-related forms (P 0.001). In contrast, disease duration was longer former (20.5 9.3 13.7, P=0.001), though similar functional stages, indicating slower progression disease. Of interest, intellectual deficiency frequent while cognitive impairment adulthood among three groups. Similar differences single gene group, comparing 23 (spinocerebellar 6) 22 point mutations, which lower (25.2 47.3 years) (18.7 10.9), but severity indexes (0.39 0.44), conclusion, variations up 15% after confirmed genes. could delineate firm are important counselling prognostic value.