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. WHAT THIS PAPER ADDS: Sodium-channel disorder heterogeneity is explained by variant-specific gene expression timing and function. Gene tolerance and location analyses aid sodium channel variant interpretation. Sodium-channel variant characteristics can contribute to clinical decision making.