Abstract
Spinocerebellar ataxia (SCA) 42 is caused by a mutation in CACNA1G, which encodes the low voltage-gated calcium channel Ca(V)3.1 (T-type). Patients with SCA42 exhibit a pure form of cerebellar ataxia. We encountered a patient with the p.Arg1715His mutation, suffering from intractable resting tremor, particularly head tremor. This symptom improved with the administration of low-dose of zonisamide (ZNS), a T-type calcium channel blocker effective for treating Parkinson's disease and epilepsy. Previous electrophysiological studies showed that the voltage dependence of this mutant Ca(V)3.1 was shifted toward the positive potential. This abnormal shift was considered a factor related to disease onset and symptoms. In this study, we performed whole-cell recordings of GFP-expressing HEK293T cells that expressed wild-type or mutant Ca(V)3.1 and investigated the changes in the abnormal shift of voltage dependence of the mutant Ca(V)3.1. The results showed that ZNS in an amount equivalent to the patient's internal dose significantly ameliorated the abnormal shift in the mutant Ca(V)3.1, giving values close to those in the wild-type. On the other hand, ZNS did not affect the voltage dependence of wild-type Ca(V)3.1. Because Ca(V)3.1 is known to be involved in tremogenesis, modulation of the voltage dependence of mutant Ca(V)3.1 by ZNS might have contributed to improvement in the intractable tremor of our patient with SCA42. Moreover, efonidipine, another T-type calcium channel blocker, had no effect on tremors in our patient with SCA42 and did not improve the abnormal shift in the voltage dependence of the mutant Ca(V)3.1. This indicates that ZNS is distinct from other T-type calcium channel blockers in terms of modulation of the voltage dependence of the mutant Ca(V)3.1.