Symposium ProceedingsSCN8A Epilepsy, Developmental Encephalopathy, and Related Disorders
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 NaV1.1 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 Nav1.6 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.
Section snippets
The SCN8A gene
The SCN8A gene, located on chromosome 12q13.13, is one of the nine human voltage-gated sodium channel genes that are important in the formation of pore-forming alpha subunits of sodium channels in cell membranes. The SCN8A gene encodes the protein of the alpha subunit of the Nav1.6 sodium channel located primarily in the central and peripheral nervous system with minor expression in the membranes of the cardiac muscle fibers.8 The Nav1.6 channel protein is located in the cell membrane and has
The index case
The index case of SCN8A epileptic encephalopathy, described in detail by Veeramah et al.,6 was identified with whole-genome sequencing on a family quartet, which included the female proband with unexplained refractory epilepsy, and developmental impairment, both unaffected parents and a brother. The proband suffered from a moderate epileptic encephalopathy and died at age 15 years from SUDEP. The genome sequencing analysis performed by the laboratory of Michael Hammer at the University of
Genetics of SCN8A encephalopathy
Evolutionarily, the transmembrane domains 1 to 4 with their segments, short loop between domains 3 and 4, and the proximal region of the cytoplasmic C terminal of the Nav1.6 channel are highly conserved. Cytoplasmic loops 1 and 2 and distal C terminus are less conserved. SCN8A gene variants causing substitution of amino acid residues in the highly conserved regions are often deleterious. Today, with the help of whole-exome and whole-genome sequencing and commercially available epilepsy gene
Phenotypic spectrum of SCN8A encephalopathy
Most SCN8A variants result in a moderate-severe epileptic encephalopathy, which is the classic manifestation of this genetic condition, and is classified as early infantile epileptic encephalopathy type 13 (OMIM). The spectrum of clinical manifestations has been reported in cohorts of patients,18,19 and SCN8A epileptic encephalopathy accounts for 1% of childhood epileptic encephalopathies.18, 19, 20, 21 Seizure onset is typically from birth to 18 months with a mean age of onset of four to five
Classification of SCN8A disorders
Based upon functional biophysical studies using voltage clamp recordings of ionic currents performed on a variety of SCN8A variants, multiple biophysical NaV1.6 defects have been identified. Zaman et al. hypothesized that the severity of clinical manifestations correlates with the number/combination of such defects, with a more prominent GoF effect leading to a more severe disease manifestation.36 Gardella and Moller reviewed the published medical literature and suggested a tripartite
Treatment of SCN8A encephalopathy
Because seizures are the primary manifestation and may contribute to developmental impairment and regression, the primary emphasis of treatment is seizure control. In contrast to Dravet syndrome, where LoF variants in SCN1A expressed on inhibitory interneurons lead to neuronal hyperactivity, GoF variants in SCN8A expressed on excitatory neurons increase neuronal excitability and cause disease. The GoF mechanism predicts that seizures are likely to respond to sodium channel blockers. Several
Conclusions
With advances in genetics and the use of whole-genome and whole-exome sequencing, the practice of child neurology has changed significantly in the twenty-first century. Many neurological diseases of childhood onset are now known to have a genetic basis. Understanding of early-onset childhood epilepsies with epileptic encephalopathy has particularly been affected by the significant progress and availability of genetic testing. Several monogenic disorders that cause epilepsy and associated
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Cited by (21)
Neurodevelopmental disorders caused by variants in TRPM3
2024, Biochimica et Biophysica Acta - Molecular Cell ResearchComplex biophysical changes and reduced neuronal firing in an SCN8A variant associated with developmental delay and epilepsy
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseEpilepsy surgery in patient with monogenic epilepsy related to SCN8A mutation
2022, Epilepsy and Behavior ReportsCitation Excerpt :Several studies reported a favorable seizure response to sodium channels drugs such as carbamazepine, oxcarbazepine, and phenytoin; high doses are often required, and treatment of seizures remains mostly inadequate. Seizures could endure intractable despite partial responses and seizure-free periods [18,19]. Our patient was heterozygous for SCN8A mutation in exon 16 (c.2671G > A, p.Val891Met).
Declarations of Interests: Dinesh Talwar, MD: None. Michael Hammer, PhD: Founder of scn8a.net and Consultant for Neurocrine Biosciences.