Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Children's Hospital and Department of Biophysics, National Clinical Research Center for Child Health, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
Mol Genet Genomic Med. 2020 Jul;8(7):e1250. doi: 10.1002/mgg3.1250. Epub 2020 May 13.
To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE).
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.
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.
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.
研究 SCN2A 相关发育性癫痫性脑病（DEE）的表型、基因型和功能型之间的关系。
我们纳入了 5 例具有 SCN2A 新出现变异的 DEE 患者。通过全细胞膜片钳记录，对在 HEK293T 细胞中表达的 Nav1.2 通道蛋白的功能分析和药理学特征进行了表征。
c.4712T>C(p. I1571T)、c.2995G>A(p.E999K)和 c.4015A>G(p. N1339D)变异的表型表现出相似的特征，包括早期发病伴有严重至重度智力障碍。电生理记录显示激活曲线的电压依赖性出现超极化偏移，快速失活的恢复时间常数较小，表明功能获得（GOF）明显。此外，药理学电生理学表明，苯妥英抑制超过 70%的峰值电流，比奥卡西平、卡马西平更有效。相比之下，c.4972C>T(p.P1658S)和 c.5317G>A(p.A1773T)导致功能丧失（LOF）改变，表现为电流密度降低和快速失活增强。两者均在 3 个月大后出现癫痫发作，伴有中度发育迟缓。有趣的是，我们发现舞蹈手足徐动症是一种特异性表型特征。
这些发现为 SCN2A 相关 DEE 的表型-基因型-功能型关系提供了深入了解。使用 GOF 和 LOF 的明显提示进行初步评估有助于计划治疗，下一步应该是进行电生理研究。
