Pathophysiology and therapy of SCN8A and CACNA1G associated ataxia
Ataxia disturbes coordination due to cerebellar dysfunction leading to disabling impairment of gait, dexterity and speech. We found heterozygous de novo variants in SCN8A and CACNA1G to cause genetic forms of ataxia. To explore the pathophysiology, we will express these variants in a heterologous system to examine their biophysical effects on channel function using whole-cell patch clamping, and we will investigate the effect of these variants on neuronal firing properties in cultured hippocampal and cerebellar neurons.
With recordings of more variants, we will establish genotype-phenotype relationships by combining clinical and experimental results. Finally, we will perform pharmacological in vitro studies to explore new therapeutic options for these neuronal disorders.