Ishii Atsushi, Watkins Joseph C, Chen Debbie, Hirose Shinichi, Hammer Michael F
ARL Division of Biotechnology, University of Arizona, Tucson, Arizona, U.S.A.
Department of Pediatrics, School of Medicine and Central Research Institute for the Molecular Pathogeneses of Epilepsy, Fukuoka University, Fukuoka, Japan.
Epilepsia. 2017 Feb;58(2):282-290. doi: 10.1111/epi.13639. Epub 2016 Dec 24.
Two major classes of SCN1A variants are associated with Dravet syndrome (DS): those that result in haploinsufficiency (truncating) and those that result in an amino acid substitution (missense). The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation-positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment.
We sequenced all exons and intron-exon boundaries of SCN1A in our cohort, investigated differences in the distribution of truncating and missense variants, tested for associations between variant type and phenotype, and compared these patterns with those of cohorts with milder epilepsy and healthy individuals.
Unlike truncation variants, missense variants are found at higher density in the S4 voltage sensor and pore loops and at lower density in the domain I-II and II-III linkers and the first three segments of domain II. Relative to healthy individuals, there is an increased frequency of truncating (but not missense) variants in the noncoding C-terminus. The rate of cognitive decline is more rapid for patients with truncation variants regardless of age at seizure onset, whereas age at onset is a predictor of the rate of cognitive decline for patients with missense variants.
We found significant differences in the distribution of truncating and missense variants across the SCN1A sequence among healthy individuals, patients with DS, and those with milder forms of SCN1A-variant positive epilepsy. Testing for associations with phenotype revealed that variant type can be predictive of rate of cognitive decline. Analysis of descriptive medication data suggests that in addition to conventional drug therapy in DS, bromide, clonazepam and topiramate may reduce seizure frequency.
SCN1A基因变异主要有两大类与德雷维特综合征（DS）相关：一类导致单倍剂量不足（截短型），另一类导致氨基酸替换（错义型）。这项回顾性研究的目的是描述日本首批大量SCN1A突变阳性DS患者队列（n = 285），并研究变异（类型和位置）与临床表型及治疗反应之间的关系。
我们对队列中SCN1A的所有外显子和内含子-外显子边界进行测序，研究截短型和错义型变异分布的差异，测试变异类型与表型之间的关联，并将这些模式与轻度癫痫患者队列和健康个体的模式进行比较。
与截短型变异不同，错义型变异在S4电压感受器和孔环中密度较高，而在结构域I-II和II-III连接区以及结构域II的前三个片段中密度较低。相对于健康个体，非编码C末端截短型（而非错义型）变异的频率增加。无论癫痫发作起始年龄如何，截短型变异患者的认知衰退速度更快，而对于错义型变异患者，发病年龄是认知衰退速度的一个预测因素。
我们发现健康个体以及DS患者和SCN1A变异阳性癫痫较轻形式患者的SCN1A序列中截短型和错义型变异的分布存在显著差异。与表型关联的测试表明，变异类型可预测认知衰退速度。对描述性用药数据的分析表明，除了DS中的传统药物治疗外，溴化物、氯硝西泮和托吡酯可能会降低癫痫发作频率。
