1. Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy.
- Author
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Miao P, Tang S, Ye J, Wang J, Lou Y, Zhang B, Xu X, Chen X, Li Y, and Feng J
- Subjects
- Action Potentials drug effects, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Child, Preschool, Developmental Disabilities diagnosis, Developmental Disabilities drug therapy, Epilepsy diagnosis, Epilepsy drug therapy, Female, Gain of Function Mutation, HEK293 Cells, Humans, Infant, Ion Channel Gating, Loss of Function Mutation, Male, NAV1.2 Voltage-Gated Sodium Channel chemistry, NAV1.2 Voltage-Gated Sodium Channel metabolism, Precision Medicine, Sodium Channel Blockers pharmacology, Sodium Channel Blockers therapeutic use, Developmental Disabilities genetics, Epilepsy genetics, NAV1.2 Voltage-Gated Sodium Channel genetics, Phenotype
- Abstract
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., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2020
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