Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy.
Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy.
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DOI：
10.1212/wnl.0000000000004762
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发表时间：
2018-01-02
期刊：
影响因子：
9.9
通讯作者：
Kurian MA
中科院分区：
文献类型：
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作者：
McTague A;Nair U;Malhotra S;Meyer E;Trump N;Gazina EV;Papandreou A;Ngoh A;Ackermann S;Ambegaonkar G;Appleton R;Desurkar A;Eltze C;Kneen R;Kumar AV;Lascelles K;Montgomery T;Ramesh V;Samanta R;Scott RH;Tan J;Whitehouse W;Poduri A;Scheffer IE;Chong WKK;Cross JH;Topf M;Petrou S;Kurian MA
表征早发性KCNT1癫痫的表型谱、分子遗传学发现和致病变异的功能后果。我们确定了31例伴有迁移性局灶性癫痫（EIMFS）的婴儿期癫痫患者队列，并使用直接Sanger测序、多基因下一代测序面板和全外显子组测序筛选KCNT1变异。我们还纳入了其他非eimfs早发性癫痫患者，这些患者在局部诊断多基因面板检测中发现了KCNT1变异。在可能的情况下，我们进行了同源性建模来预测变异对蛋白质结构和功能的可能影响。我们在爪蟾卵母细胞模型系统中对突变KCNT1通道进行了电生理评估。我们在12例患者中发现了KCNT1的致病变异，其中4例是新的。大多数变异都是从头开始的。10例临床诊断为EIMFS，另外2例表现为早发性重度夜间额叶癫痫发作。3例患者进行了奎尼丁试验，1例患者临床反应良好。计算模型分析暗示异常孔隙功能（F346L）和受损的四聚体形成（F502V）可能是疾病机制。所有评估的KCNT1变异都导致功能显著增加，通道振幅显著增加，并被奎尼丁阻断。功能获得性KCNT1致病变异可引起婴幼儿早期发病的一系列严重局灶性癫痫。目前，基因型与表型的相关性尚不清楚，尽管大多数病例的临床结果很差。进一步阐明疾病机制可能有助于开发针对这种耐药遗传性癫痫的靶向治疗方法。
To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.