SCN8A Epilepsy, Developmental Encephalopathy, and Related Disorders

Abstract

Understanding the precise genetic -basis of disease is one of the critical developments in medicine in the twenty-first century. Genetic testing has revolutionized the diagnosis and treatment of neurological diseases in children. Whole-genome and whole-exome sequencing have particularly been useful in understanding the genetic basis of childhood epileptic encephalopathies characterized by early-onset seizures with significant developmental impairment and regression. In this review we describe the identification of a new epileptic encephalopathy caused by a de novo mutation in the SCN8A gene, which encodes for Na_V1.6, a vital sodium channel in the central nervous system. SCN8A variants in patients with epilepsy result primarily in gain-of-function in Na_v1.6 and hyperexcitability of neurons in the central nervous system. Following the original discovery in 2012 of a de novo mutation in a child with developmental and epileptic encephalopathy (DEE), more than 400 individuals with SCN8A-related disorders have been identified. Clinical manifestations range from movement disorders or intellectual disability only to severe DEE, which includes epileptic encephalopathy with intractable multivariate seizure types, developmental impairment and regression, intellectual disability, and other neurological manifestations. Gain-of-function of the Na_v1.6 channel predicts effectiveness of sodium channel-blocking agents in the treatment of seizures, which has been corroborated by clinical experience. Nevertheless, treatment options remain limited and adverse effects are common. However, with the availability of a growing database of genetic and clinical data along with transfected cell lines and mouse models, more efficacious, targeted, and selective treatments may soon be feasible.

Introduction

Kenneth F. Swaiman (1931 to 2020) with his contributions to medicine is remembered as one of the founders of child neurology. Ken Swaiman, and the early founders, established child neurology as a distinct specialty and contributed greatly to the development of our understanding of neurological conditions in children. Although much of the early progress in child neurology was due to the clinical acumen and rigorous clinical study by dedicated clinicians, the discipline of pediatric neurology has evolved over the years. In the latter part of the twentieth century the development of imaging using computed tomography and magnetic resonance technology promoted understanding of the structural basis of many neurological disorders in children, advancing diagnostic and therapeutic tools. In the twenty-first century there has been greater emphasis and explosion of information on understanding the precise genetic basis of disease. Ken Swaiman had a specific interest in the clinical manifestations and pathophysiologic mechanisms underlying pantothenate kinase-associated neurodegeneration, recognized as an autosomal recessive condition.^1,2 The early clinical descriptions of this disorder led to the discovery of the PANK2 gene encoding the enzyme pantothenate kinase 2, responsible for the synthesis of coenzyme A important for energy metabolism in the mitochondria.³ Similarly Charlotte Dravet described the clinical features of a distinctive epilepsy syndrome in 1978, now well known as Dravet syndrome.⁴ The accurate phenotypic description of this syndrome led to the discovery of SCN1A gene, regulating voltage-gated sodium channels Na_V1.1 in the central nervous system, as the primary causative gene of Dravet syndrome.⁵

Many neurological conditions in children have diverse, nonuniform, clinical manifestations, and as a result, a multitude of etiologies. Understanding the etiology of severe epilepsies of childhood onset has been a challenge for many years, and they have often been lumped into broad syndromes such as early infantile epileptic encephalopathy, infantile spasms or West syndrome, Lennox-Gastaut syndrome, etc. With the advent of readily available whole-genome and whole-exome sequencing performed on probands and parents, a variety of gene variants have been discovered that helped to identify the etiology and pathophysiology of severe epileptic encephalopathies in children. Using a whole-genome sequencing approach in a family quartet, a distinct pathogenic variant of SCN8A gene was discovered in 2012 as a cause of unexplained epileptic encephalopathy in a 15-year-old girl, who had intractable seizures, intellectual disability, developmental impairment and regression, and SUDEP (sudden unexplained death in epilepsy).⁶ Biophysical studies on transfected neurons helped understand the pathophysiologic mechanism underlying the seizure disorder. Subsequently, an online SCN8A registry with a detailed questionnaire was established in 2015 at the University of Arizona, which has gathered medical, developmental, and genetic information from more than 350 patients,⁷ and the number of known cases of individuals with pathogenic variants in SCN8A has grown to more than 400. Although SCN8A developmental and epileptic encephalopathy (DEE) is a distinct condition with genetic variants affecting voltage-gated Na_v1.6 channels in the central nervous system, clinical manifestations are variable and range from benign or mild childhood epilepsy to a severe epileptic encephalopathy. Conditions such as SCN8A encephalopathy help us understand the genotypic and phenotypic variability of disease encoded by a single gene.