Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.

Ibitayo Abigail Ademuwagun,Yvonne Ukamaka Ajamma,Steffen Syrbe,Solomon Oladapo Rotimi,Ezekiel Adebiyi

doi:10.3389/fneur.2021.600050

Ibitayo Abigail Ademuwagun, Yvonne Ukamaka Ajamma + Show 3 more

Open Access

https://doi.org/10.3389/fneur.2021.600050

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Abstract

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

Highlights

Epilepsy is a neurological disorder with spontaneous and re-occurring seizures that are borne from a population of cortical neurons, exhibiting hyper-synchronized discharge of high current action potentials in the brain [1, 2]
Lagae et al [70] reported the outcome of a Phase III clinical trial which suggests that the drug is safe for use as a combination drug at low doses (
Since epilepsy is a polygenic and heterogenous disorder, the increasingly cheap cost of whole genome and exome sequencing is rapidly advancing variant identification in candidate genes, including those acting as disease modifiers

Summary

INTRODUCTION

Epilepsy is a neurological disorder with spontaneous and re-occurring seizures that are borne from a population of cortical neurons, exhibiting hyper-synchronized discharge of high current action potentials in the brain [1, 2]. Voltage gated sodium ion channels (VGSCs) are heteromeric proteins involved in the generation and propagation of action potentials in brain neural cells [7]. They are membraneassociated proteins and are responsible for conducting currents of sodium ions down their concentration gradient into the cell [8] Mutations associated with these channel genes are the most common cause of genetic epilepsies, with thousands of them reported in diverse populations [9]. Sulfonamides with anticonvulsant properties, quantitative structure activity relationship (QSAR) models for VGSC functions, biomarker studies in epilepsy syndromes and clinical trials of AEDs. There are nine different sodium channel α-subunit genes that code for Nav1.1 to Nav1.9 [12] channel proteins.

CONCLUSION AND FUTURE

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