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

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.

SUBMITTER: Miao P

PROVIDER: S-EPMC7336724 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Miao Pu P Tang Siyang S Ye Jia J Wang Jianda J Lou Yuting Y Zhang Bijun B Xu Xiaoxiao X Chen Xiaoquan X Li Yuezhou Y Feng Jianhua J

Molecular genetics & genomic medicine 20200513 7

<h4>Background</h4>To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE).<h4>Methods</h4>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.<h4>Results</h4>The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D ...[more]

PMID: 32400968

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Project description:Key pointsThe recurrent SCN2A mutation R853Q is associated with developmental and epileptic encephalopathy with typical onset after the first months of life. Heterologously expressed R853Q channels exhibit an overall loss-of-function as a result of multiple defects in time- and voltage-dependent channel properties. A previously unrecognized enhancement of slow inactivation is conferred by the R853Q mutation and is a major driver of loss-of-function. Enhanced slow inactivation is potentiated in the canonical splice isoform of the channel and this may explain the later onset of symptoms associated with R853Q.AbstractMutations in voltage gated sodium (NaV ) channel genes, including SCN2A (encoding NaV 1.2), are associated with diverse neurodevelopmental disorders with or without epilepsy that present clinically with varying severity, age-of-onset and pharmacoresponsiveness. We examined the functional properties of the most recurrent SCN2A mutation (R853Q) to determine whether developmentally-regulated alternative splicing impacts dysfunction severity and to investigate effects of the mutation on slow inactivation. We engineered the R853Q mutation into neonatal and adult NaV 1.2 splice isoforms. Channel constructs were heterologously co-expressed in HEK293T cells with human β1 and β2 subunits. Whole-cell patch clamp recording was used to compare time- and voltage-dependent properties of mutant and wild-type channels. The R853Q mutation exhibits an overall loss-of-function attributed to multiple functional defects including a previously undiscovered enhancement of slow inactivation. The mutation exhibited altered voltage dependence of activation and inactivation, slower recovery from inactivation and decreased channel availability during high-frequency depolarizations. More notable were effects on slow inactivation, including a 10-fold slower rate of recovery from slow inactivation exhibited by mutant channels. The impairments in fast inactivation properties were more severe in the neonatal splice isoform, whereas slow inactivation was more pronounced in the splice isoform of the channel expressed predominantly in later childhood. Enhanced later-onset slow inactivation may be a primary driver of the later onset of neurological features associated with this mutation.

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

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

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