Spinocerebellar ataxia (SCA) 42 is caused by a mutation in CACNA1G, which encodes the low voltage-gated calcium channel CaV3.1 (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 CaV3.1 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 CaV3.1 and investigated the changes in the abnormal shift of voltage dependence of the mutant CaV3.1. The results showed that ZNS in an amount equivalent to the patient’s internal dose significantly ameliorated the abnormal shift in the mutant CaV3.1, giving values close to those in the wild-type. On the other hand, ZNS did not affect the voltage dependence of wild-type CaV3.1. Because CaV3.1 is known to be involved in tremogenesis, modulation of the voltage dependence of mutant CaV3.1 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 CaV3.1. This indicates that ZNS is distinct from other T-type calcium channel blockers in terms of modulation of the voltage dependence of the mutant CaV3.1.

中文翻译：

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唑尼沙胺可以改善由导致脊髓小脑性共济失调的突变引起的 T 型钙通道 CaV3.1 的电压依赖性改变

脊髓小脑性共济失调 (SCA) 42 是由 CACNA1G 突变引起的，该突变编码低电压门控钙通道 CaV3.1（T 型）。SCA42 患者表现出纯形式的小脑性共济失调。我们遇到了一位患有 p.Arg1715His 突变的患者，患有顽固性静止性震颤，尤其是头部震颤。这种症状在服用低剂量唑尼沙胺 (ZNS) 后得到改善，ZNS 是一种 T 型钙通道阻滞剂，可有效治疗帕金森病和癫痫症。先前的电生理研究表明，这种突变体 CaV3.1 的电压依赖性向正电位转移。这种异常转变被认为是与疾病发作和症状有关的一个因素。在这项研究中，我们对表达野生型或突变型 CaV3 的表达 GFP 的 HEK293T 细胞进行了全细胞记录。1 并研究了突变体 CaV3.1 电压依赖性异常变化的变化。结果表明，相当于患者体内剂量的 ZNS 显着改善了突变 CaV3.1 的异常变化，其值接近野生型。另一方面，ZNS 不影响野生型 CaV3.1 的电压依赖性。因为已知 CaV3.1 参与震颤，所以 ZNS 对突变 CaV3.1 的电压依赖性的调节可能有助于改善我们患有 SCA42 的患者的顽固性震颤。此外，另一种 T 型钙通道阻滞剂依福地平对 SCA42 患者的震颤没有影响，也没有改善突变 CaV3.1 电压依赖性的异常变化。