Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies
Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies
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DOI：
10.1002/humu.23619
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发表时间：
2018-12-01
期刊：
影响因子：
3.9
通讯作者：
Hedrich, Ulrike B. S.
中科院分区：
文献类型：
--
作者：
Lauxmann, Stephan;Verbeek, Nienke E.;Hedrich, Ulrike B. S.
SCN 2A基因的变异体可引起多种严重程度不同的癫痫综合征，包括良性脑-婴儿癫痫（BFNIE）、发育性和癫痫性脑病（DEE）和其他神经精神疾病。在这里，我们研究了三个新发现的变异，这引起了不同的表型观察到9个受影响的个人的三个家庭，包括BFNIE，和DEE与顽固性新生儿癫痫发作。转染tsA 201细胞的全细胞膜片钳记录揭示了在动作电位刺激时增加的电流密度和增加的阈下钠内向电流（p.（Lys 908 Glu））、激活曲线的超极化移位（p.（Val 208 Glu）和p.（Thr 773 Ile））和增加的持续电流（p.（Thr773Ile））。为了评估基因型-表型的相关性，我们接下来开发了电生理功能障碍程度和临床表型严重程度的评分系统，并将其应用于21种先前和新功能表征的SCN 2A变体。所有遗传变异与轻度临床表型和较低的电生理评分相比，发生从头和导致严重的表型。因此，我们的研究结果揭示了通道功能障碍的程度和临床严重程度之间的良好相关性。
Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p.(Lys908Glu)), a hyperpolarizing shift of the activation curve (p.(Val208Glu) and p.(Thr773Ile)), and an increased persistent current (p.(Thr773Ile)). To evaluate genotype-phenotype correlations, we next developed scoring systems for both the extent of the electrophysiological dysfunction and the severity of the clinical phenotype and applied those to 21 previously and newly functionally characterized SCN2A variants. All inherited variants were associated with a mild clinical phenotype and a lower electrophysiological score compared to those occurring de novo and causing severe phenotypes. Our results thus reveal a nice correlation between the extent of channel dysfunction and the clinical severity.