Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy

Abstract

BackgroundTo investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A‐related developmental epileptic encephalopathy (DEE).MethodsWe 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.ResultsThe 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.ConclusionThese 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.

Hyperexcitability and Pharmacological Responsiveness of Cortical Neurons Derived from Human iPSCs Carrying Epilepsy-Associated Sodium Channel Nav1.2-L1342P Genetic Variant

“…Several recently reported variants in SCN2A from patients with childhood epilepsy also presented with evidence indicating developmental impairments (Miao et al, 2020). The terminology of "developmental and/or epileptic encephalopathy" thus has been used to imply that the developmental impairments could occur independently of seizures (Maljevic et al, 2017;Scheffer et al, 2017).…”

Sodium channel Nav1.2-L1342P variant displaying complex biophysical properties renders hyperexcitability of cortical neurons derived from human iPSCs

“…Several recently reported variants in SCN2A from patients with childhood epilepsy also presented with evidence indicating developmental impairments. 68 The terminology of "developmental and/or epileptic encephalopathy" thus has been used to imply that the developmental impairments could occur independently of seizures. 69,70 Indeed, profiling of patients with the L1342P variant revealed developmental disorders.…”

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

“…At present, voltage-gated sodium channel genes such as SCN1A , SCN2A , SCN3A , and SCN8A were reported to be causative genes of epilepsy ( Ademuwagun et al, 2021 ), among them SCN2A has been reported to be the second most common, next only to SCN1A , the first reported causative gene for epilepsy ( Heyne et al, 2019 ). Epilepsy caused by SCN2A variants mostly starts in early childhood and has a wide phenotypic spectrum, ranging from self-limited epilepsy with a favorable outcome to developmental and epileptic encephalopathy, and most of them respond well to sodium channel blockers (SCBs) ( Grinton et al, 2015 ; Trump et al, 2016 ; Dilena et al, 2017 ; Flor-Hirsch et al, 2018 ; Kim et al, 2020 ; Melikishvili et al, 2020 ; Miao et al, 2020 ; Penkl et al, 2021 ). China has a large population and a large number of epilepsy children.…”