Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy
Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy
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电生理学特征：SCN2A 发育性癫痫性脑病的下一步
DOI：
10.1002/mgg3.1250
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发表时间：
2020-05-13
影响因子：
2
通讯作者：
Feng, Jianhua
中科院分区：
文献类型：
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作者：
Miao, Pu;Tang, Siyang;Feng, Jianhua
背景探讨SCN 2A相关发育性癫痫脑病（DEE）的表型、基因型和功能型之间的关系。结果c.4712T>C（p.I1571T）、c.2995G>A（p.E999K）和c.4015A>G（p.N1339D）变异体具有相似的表型，包括早期癫痫发作和严重至极重度智力障碍。电生理记录显示，超极化转变的电压依赖性的激活曲线和较小的恢复时间常数的快速失活比野生型，表明一个突出的增益功能（GOF）。此外，药理电生理学表明，苯妥英钠抑制超过70%的峰值电流，比奥卡西平和卡马西平更有效。相反，c.4972C>T（p.P1658S）和c.5317G>A（p.A1773T）导致功能丧失（LOF）变化，显示出降低的电流密度和增强的快速失活。两例均在3月龄后癫痫发作，伴有中度发育延迟。有趣的是，我们发现舞蹈手足徐动症是一个特定的表型特征。结论这些发现提供了深入了解SCN 2A相关DEE的表型-基因型-功能型关系。使用GOF和LOF的不同提示进行初步评估有助于制定治疗计划，下一步应该是电生理学研究。
Background To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE).Methods We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole-cell patch-clamp recording.Results The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast-inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature.Conclusion These findings provided the insights into the phenotype-genotype-funotype relationships of SCN2A-related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.