V374A KCND3 pathogenic variant associated with paroxysmal ataxia exacerbations

Objective

Ataxia channelopathies share common features such as slow motor progression and variable degrees of cognitive dysfunction. Mutations in KCND3, encoding the K+ channel, Kv4.3, are associated with spinocerebellar ataxia 19 (SCA19), allelic with spinocerebellar ataxia 22 (SCA22). Mutations in KCNC3, encoding another K+ channel, Kv3.3, cause spinocerebellar ataxia 13 (SCA13). First, a comprehensive phenotype assessment was carried out in a family with autosomal dominant ataxia harboring two genetic variants in KCNC3 and KCND3. In order to evaluate the physiological impact of these variants on channel currents, in vitro studies were performed.

Methods

Clinical and psychometric evaluations, neuroimaging, and genotyping of a family (mother and son) affected by ataxia were carried out. Heterozygous and homozygous Kv3.3 A671V andKv4.3 V374A variants were evaluated in Xenopus laevis oocytes using two-electrode voltage-clamp. The influence of Kv4 conductance on neuronal activity...