Molecular pathophysiology of SCN5A-related cardiac arrhythmias in children: phenotype spectrum and potential therapeutic targets
Year: 2025
Type: article
Abstract: Pathogenic variants in SCN5A, encoding the cardiac sodium channel Nav1.5, are responsible for a diverse spectrum of potentially life-threatening arrhythmias in children. This review examines the molecular pathophysiology of SCN5A-related cardiac disorders in the pediatric population, focusing on genotype–phenotype correlations and emerging therapeutic approaches. Nav1.5 channels, with their complex four-domain structure, orchestrate the cardiac action potential by precisely regulating sodium currents. Mutations cause either gain-of-function effects (enhancing late sodium current) leading to Long QT Syndrome type 3, or loss-of-function effects (reducing channel availability or conductance) underlying Brugada syndrome, progressive cardiac conduction disease, and sick sinus syndrome. Notably, pediatric presentations often feature a high prevalence of conduction disorders and overlap syndromes, with diagnosis before one year of age and compound heterozygosity conferring particularly high risk. Advanced therapeutic strategies are evolving beyond conventional treatments, including mutation-specific pharmacotherapy (ranolazine, mexiletine), gene and RNA therapies (CRISPR/Cas9, antisense oligonucleotides), and cell-based approaches using induced pluripotent stem cell-derived cardiomyocytes. These precision medicine approaches hold promise for transforming the management of these disorders, though significant challenges remain in ensuring safety, efficacy, and equitable access, particularly for pediatric patients.
Authors: Nguyen Bao Hanh, Tran Thuy Duong, Do Tien Son
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4415296375