Kobayashi Takahashi Yoko, Tabata Kenshiro, Baba Shimpei, Takeshita Eri, Sumitomo Noriko, Shimizu-Motohashi Yuko, Saito Takashi, Nakagawa Eiji, Ishii Atsushi, Hirose Shinichi, Kato Mitsuhiro, Matsumoto Naomichi, Komaki Hirofumi, Inoue Ken
Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Epilepsia Open. 2025 Jun 18. doi: 10.1002/epi4.70080.
A large number of cases with Dravet syndrome (DS) has been attributed to SCN1A loss of function (LOF), whereas SCN1A gain-of-function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individuals with SCN1A pathogenic variants at our institute between January 2012 and October 2024 to investigate phenotype-function correlations. Variant functions were classified as LOF, GOF, or mixed, based on existing patch-clamp data, paralog sodium channel experimental findings, and in silico prediction tools. Clinical characteristics, antiseizure medication (ASM) responses, and variant location were compared. Nine variants were novel. One variant with insufficient data for functional prediction was excluded. Of the 36 cases with predictable functions, five cases (14%) were classified as GOF/mixed (DS = 4, EIDEE = 1) and 31 (86%) as LOF (DS = 31). GOF/mixed-DS had earlier epilepsy onset but otherwise resembled LOF-DS. Sodium channel blocking ASMs (SCB-ASMs) did not exacerbate seizures in GOF/mixed DS cases, with carbamazepine reducing seizures in one case. GOF/mixed variants clustered in the intracellular S6 segment, whereas LOF variants clustered in the S5-S6 pore loop. These findings highlight a potential GOF effect for certain DS cases, suggesting that SCB-ASMs may be effective for GOF/mixed DS. This underscores the importance of functional characterization for tailored therapy, warranting further research to confirm and extend these results. PLAIN LANGUAGE SUMMARY: Dravet syndrome is a severe epilepsy that usually begins in infancy and is linked to changes in a gene called SCN1A. Most cases are caused by gene changes that reduce function, but in some cases, the gene may become overactive. In this study, we found that some patients with Dravet syndrome had these overactive changes and still showed typical symptoms. We found that people with overactive SCN1A function might respond differently to certain medications.
大量的德拉韦特综合征（DS）病例被归因于SCN1A功能丧失（LOF），而SCN1A功能获得（GOF）则导致早发性婴儿发育性癫痫性脑病（EIDEE）和家族性偏瘫性偏头痛3型。我们回顾性分析了2012年1月至2024年10月在我院的37例携带SCN1A致病变异的个体，以研究表型与功能的相关性。根据现有的膜片钳数据、旁系钠通道实验结果和计算机预测工具，将变异功能分为功能丧失、功能获得或混合型。比较了临床特征、抗癫痫药物（ASM）反应和变异位置。9个变异为新发现。排除1个功能预测数据不足的变异。在36例功能可预测的病例中，5例（14%）被归类为功能获得/混合型（DS = 4例，EIDEE = 1例），31例（86%）为功能丧失型（DS = 31例）。功能获得/混合型DS的癫痫发作起始更早，但其他方面与功能丧失型DS相似。钠通道阻断性抗癫痫药物（SCB-ASM）在功能获得/混合型DS病例中并未加重癫痫发作，卡马西平在1例中减少了癫痫发作。功能获得/混合型变异聚集在细胞内S6段，而功能丧失型变异聚集在S5-S6孔环。这些发现突出了某些DS病例存在潜在的功能获得效应，提示SCB-ASM可能对功能获得/混合型DS有效。这强调了功能特征化对个体化治疗的重要性，需要进一步研究以证实和扩展这些结果。通俗易懂的总结：德拉韦特综合征是一种严重的癫痫，通常始于婴儿期，与一种名为SCN1A的基因变化有关。大多数病例是由降低功能的基因变化引起的，但在某些情况下，该基因可能变得过度活跃。在本研究中，我们发现一些德拉韦特综合征患者有这些过度活跃的变化，但仍表现出典型症状。我们发现SCN1A功能过度活跃的人对某些药物的反应可能不同。
