Sodium channel epilepsies and neurodevelopmental disorders: from disease mechanisms to clinical application

Genetic variants in brain‐expressed voltage‐gated sodium channels (SCNs) have emerged as one of the most frequent causes of Mendelian forms of epilepsy and neurodevelopmental disorders (NDDs). This review explores the biological concepts that underlie sodium channel NDDs, explains their phenotypic heterogeneity, and appraises how this knowledge may inform clinical practice. We observe that excitatory/inhibitory neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain development, homeostasis, and neurological diseases. We hypothesize that a detailed understanding of gene expression, variant tolerance, location, and function, as well as timing of seizure onset can aid the understanding of how variants in SCN1A, SCN2A, SCN3A, and SCN8A contribute to seizure aetiology and inform treatment choice. We propose a model in which variant type, development‐specific gene expression, and functions of SCNs explain the heterogeneity of sodium channel associated NDDs. Understanding of basic disease mechanisms and detailed knowledge of variant characteristics have increasing influence on clinical decision making, enabling us to stratify treatment and move closer towards precision medicine in sodium channel epilepsy and NDDs.

• Publication year

  2020

• Venue

  Developmental Medicine & Child Neurology

• Publication date

  2020-03-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1111/dmcn.14519PMID 32227486
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

  2020influential reference
• Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

  2020cited by this paper
• Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

  2019cited by this paper
• Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes

  2019cited by this paper
• Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders.

  2019cited by this paper
• Progress in Understanding and Treating SCN2A-Mediated Disorders.

  2018cited by this paper
• Mutations in SCN3A cause early infantile epileptic encephalopathy

  2018cited by this paper
• Relationship of electrophysiological dysfunction and clinical severity in SCN2A‐related epilepsies

  2018cited by this paper
• Location: A surrogate for personalized treatment of sodium channelopathies

  2018cited by this paper
• Loss-of-function variants of SCN8A in intellectual disability without seizures

  2017cited by this paper
• SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures

  2017cited by this paper
• SCN3A deficiency associated with increased seizure susceptibility.

  2017cited by this paper
• Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.

  2017cited by this paper
• Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome

  2017cited by this paper
• Pathophysiological mechanisms of migraine and epilepsy: Similarities and differences.

  2017cited by this paper
• Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

  2017cited by this paper
• Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

  2017influential reference
• In utero seizures revealing dentato‐olivary dysplasia caused by SCN2A mutation

  2017cited by this paper
• Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation

  2016cited by this paper
• Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells

  2016cited by this paper
• Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy

  2015cited by this paper
• Targeted augmentation of nuclear gene output

  2015cited by this paper
• 'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour.

  2015cited by this paper
• The phenotypic spectrum of SCN8A encephalopathy

  2015cited by this paper
• Dravet syndrome—From epileptic encephalopathy to channelopathy

  2014cited by this paper
• Genotype phenotype associations across the voltage-gated sodium channel family

  2014cited by this paper
• Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome

  2013cited by this paper
• Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome.

  2012cited by this paper
• Genotype–phenotype associations in SCN1A-related epilepsies

  2011cited by this paper
• Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy.

  2010cited by this paper
• SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis

  2009cited by this paper
• The SCN1A variant database: a novel research and diagnostic tool

  2009cited by this paper
• Deletion of the SCN gene cluster on 2q24.4 is associated with severe epilepsy: an array-based genotype-phenotype correlation and a comprehensive review of previously published cases.

  2008cited by this paper
• Microchromosomal deletions involving SCN1A and adjacent genes in severe myoclonic epilepsy in infancy

  2008cited by this paper
• The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy.

  2007cited by this paper
• Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation

  2007cited by this paper
• Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy

  2006cited by this paper
• Impaired Firing and Cell-Specific Compensation in Neurons Lacking Nav1.6 Sodium Channels

  2006influential reference
• Microdeletions involving the SCN1A gene may be common in SCN1A‐mutation‐negative SMEI patients

  2006cited by this paper
• Severe myoclonic epilepsy in infancy: Dravet syndrome.

  2005cited by this paper
• Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.

  2004cited by this paper
• Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia

  2004cited by this paper
• A Nonsense Mutation of the Sodium Channel Gene SCN2A in a Patient with Intractable Epilepsy and Mental Decline

  2004cited by this paper
• De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.

  2001cited by this paper
• Phylogeny of ion channels: clues to structure and function.

  2001cited by this paper
• From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.

  2000influential reference
• Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial

  2000cited by this paper
• Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group.

  2000cited by this paper
• Type I and type II Na+ channel α‐subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain

  1999cited by this paper
• Lamotrigine and Seizure Aggravation in Severe Myoclonic Epilepsy

  1998cited by this paper
• A quantitative description of membrane current and its application to conduction and excitation in nerve

  1952cited by this paper

• Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective

  2025influential citation
• From Symptomatic Therapies to Disease-Modifying Approaches for Neuronal Sodium Channel Disorders

  2025influential citation
• Traditional Chinese Medicine Treatment for Epilepsy: Focusing on Voltage-Gated Ion Channels.

  2025cites this paper
• Identification of mutations in five Pakistani families with Epilepsy

  2025cites this paper
• Transcriptomic analyses of human brains with Alzheimer's disease identified dysregulated epilepsy-causing genes.

  2025cites this paper
• Genome-wide association meta-analyses of drug-resistant epilepsy

  2025cites this paper
• Recent advances in RNA-based therapeutics for neurodevelopmental disorders.

  2025cites this paper
• Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.

  2025cites this paper
• Transcriptomic analyses of human brains with Alzheimer’s disease identified dysregulated epilepsy-causing genes

  2025cites this paper
• Seizure worsening in SCN1A-associated Dravet syndrome while on cenobamate: case series and literature review. English version

  2025cites this paper
• Precision medicine for sodium channelopathy-related autism and epilepsy.

  2025cites this paper
• Anfallszunahme beim SCN1A-assoziierten Dravet-Syndrom unter Cenobamat: Fallserie und Literaturübersicht

  2025cites this paper
• Neurogenetic biomarkers in epilepsy: A comprehensive narrative review of progression and therapeutic approaches.

  2025cites this paper
• Unraveling Dravet Syndrome: Exploring the complex effects of sodium channel mutations on neuronal networks

  2024cites this paper
• High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study

  2024cites this paper
• The Biallelic Inheritance of Two Novel SCN1A Variants Results in Developmental and Epileptic Encephalopathy Responsive to Levetiracetam

  2024cites this paper
• Unraveling the genetic basis of epilepsy: Recent advances and implications for diagnosis and treatment.

  2024cites this paper
• Genotypic and phenotypic characteristics of sodium channel—associated epilepsy in Chinese population

  2024cites this paper
• SCN1A Channels a Wide Range of Epileptic Phenotypes: Report of Novel and Known Variants with Variable Presentations

  2024cites this paper
• Voltage-Gated Ion Channel Compensatory Effect in DEE: Implications for Future Therapies

  2024cites this paper
• Voltage‐gated sodium channels in genetic epilepsy: up and down of excitability

  2023cites this paper
• Precision Medicine in Epilepsy Management; GET Application (Gene, Epilepsy, Treatment)

  2023cites this paper
• Channelopathies in Epilepsy: from Precision Medicine to Gene Therapy

  2023influential citation
• Expression and electrophysiological characteristics of VGSC during mouse myoblasts differentiation.

  2023cites this paper
• Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.

  2022cites this paper
• Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies

  2022cites this paper
• The clinical and genetic features of SCN 1 A , SCN 2 A gene related phenotypes in patients with epilepsy and intellectual / developmental disability

  2022cites this paper
• The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

  2021cites this paper
• Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

  2021influential citation
• Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation.

  2021cites this paper
• Prognostic factors for the recurrence of afebrile seizures after benign convulsions associated with mild gastroenteritis

  2021cites this paper
• Rational Small Molecule Treatment for Genetic Epilepsies

  2021cites this paper
• No evidence that SCN9A variants are associated with epilepsy.

  2021cites this paper
• Genetics and gene therapy in Dravet syndrome.

  2021cites this paper
• Differential Functional Changes of Nav1.2 Channel Causing SCN2A-Related Epilepsy and Status Epilepticus During Slow Sleep

  2021cites this paper
• SCN1A and Its Related Epileptic Phenotypes

  2021cites this paper
• Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort.

  2021cites this paper
• Exome hits demystified: The next frontier.

  2021cites this paper
• SCN2A and Its Related Epileptic Phenotypes

  2021cites this paper
• The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity

  2021cites this paper
• Recent advances in gene therapy for neurodevelopmental disorders with epilepsy

  2020cites this paper
• Developmental and epileptic encephalopathies: Is prognosis related to different epileptic network dysfunctions?

  2020cites this paper
• Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

  2020cites this paper
• Ion channels involvement in neurodevelopmental disorders.

  2020cites this paper