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

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.

Clinical Characteristics and Treatment Experience of Individuals with SCN8A Developmental and Epileptic Encephalopathy (SCN8A-DEE): Findings from an Online Caregiver Survey

“…SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) is a rare and serious genetic epilepsy syndrome characterized by early-onset developmental delay and regression, cognitive impairment, and multiple intractable seizure types. [1][2][3] The SCN8A gene is highly expressed in the central nervous system and encodes the Nav1.6 voltage-gated sodium ion channel, which has a major role in regulating the excitatory neuronal networks in the brain. [1][2][3] The first human epileptogenetic SCN8A mutation to be identified was a missense gain-offunction mutation that altered the biophysical properties of the Nav1.6 sodium channel, as reported by Veeramah et al in 2012.…”

“…[1][2][3] The SCN8A gene is highly expressed in the central nervous system and encodes the Nav1.6 voltage-gated sodium ion channel, which has a major role in regulating the excitatory neuronal networks in the brain. [1][2][3] The first human epileptogenetic SCN8A mutation to be identified was a missense gain-offunction mutation that altered the biophysical properties of the Nav1.6 sodium channel, as reported by Veeramah et al in 2012. [4][5][6] Subsequent studies have confirmed the critical role of SCN8A in the initiation and propagation of action potentials and neuronal activity in the brain, and almost 400 individuals with SCN8A-related epilepsy have been described in the literature or documented in registries.…”

“…[4][5][6] Subsequent studies have confirmed the critical role of SCN8A in the initiation and propagation of action potentials and neuronal activity in the brain, and almost 400 individuals with SCN8A-related epilepsy have been described in the literature or documented in registries. [1][2][3]5,[7][8][9][10] The majority of documented SCN8A mutations are de novo gain-of-function mutations that result in premature channel opening, impaired inactivation, or elevated persistent current. [1][2][3]5,7 Loss-of-function variants associated with a reduction of peak current have also been reported and are typically characterized by less severe phenotypes, including less severe developmental delay, cognitive impairment, movement disorder (e.g., myoclonus), and mild or no seizures.…”

“…[1][2][3]5,[7][8][9][10] The majority of documented SCN8A mutations are de novo gain-of-function mutations that result in premature channel opening, impaired inactivation, or elevated persistent current. [1][2][3]5,7 Loss-of-function variants associated with a reduction of peak current have also been reported and are typically characterized by less severe phenotypes, including less severe developmental delay, cognitive impairment, movement disorder (e.g., myoclonus), and mild or no seizures. 1,11,12 Although rapid progress continues to be made in the functional and phenotypic classification of SCN8A-related epilepsy, an understanding of its clinical presentation, progression, prognosis, and impact is just beginning to emerge.…”

“…[1][2][3] Pathogenic SCN8A mutations have been associated with a broad phenotypic spectrum and varying degrees of disease severity, ranging from movement disorders or intellectual disability (with or without seizures) to severe DEE. [1][2][3][13][14][15][16] Individuals with less severe or "intermediate" DEE may have extended seizure-free periods, mild-to-moderate developmental delay, and mild or absent neurological deficits, while those with the most severe DEE tend to have multiple seizure types which do not or only insufficiently respond to treatment, severe and progressive physical and cognitive impairment, and increased rates of early mortality. [1][2][3][13][14][15]17 The most common seizure type in individuals with SCN8A-related epilepsies is generalized tonic/clonic, although partial/focal, absence, myoclonic, and atonic seizures have also been reported.…”