De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy With Contractures, Macrocephaly, and Dyskinesias Helbig KL, Lauerer RJ, Bahr JC, et al. Am J Hum Genet. 2019;104(3):562. Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on electroencephalogram (EEG), and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high-voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all 4 S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the antiepileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

中文翻译：

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癫痫病中的钙通道功能异常：CACNA1E的获得。

CACNA1E中的De Novo致病变异引起挛缩，大头畸形和运动障碍的发展性和癫痫性脑病Helbig KL，Laurer RJ，Bahr JC等。我是J Hum Genet。2019; 104（3）：562。发育性和癫痫性脑病（DEE）是严重的神经发育性疾病，通常始于婴儿期或儿童早期，其特征在于顽固性癫痫发作，脑电图（EEG）上癫痫样活动丰富，发育障碍或消退。CACNA1E在中枢神经系统中高度表达，并编码电压门控CaV2.3通道的α1亚基，该通道传导高压激活的R型钙电流，从而启动突触传递。使用下一代测序技术，我们在30名患有DEE的个体中鉴定了从头CACNA1E变异，其特征是顽固性婴儿发作，严重的肌张力低下和严重的发育障碍，通常伴有先天性挛缩，大头畸形，运动亢进症和早期死亡。14个部分重复的变体中的大多数都聚集在所有4个S6节段的胞质末端内，这形成了推测的CaV2.3通道激活门。几个S6变体的功能分析显示一致的功能增益效应，包括促进的电压依赖性激活和缓慢的失活。位于结构域II S4-S5接头中的另一个变体导致促进活化和增加电流密度。五名参与者在抗癫痫药托吡酯上获得了癫痫发作的自由，该药物可阻断R型钙通道。