REVIEW article
Front. Neurosci.
Sec. Neurodegeneration
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1634718
Dravet Syndrome: Novel Insights into SCN1A-Mediated Epileptic Neurodevelopmental Disorders within the Molecular Diagnostic-Therapeutic Framework
Provisionally accepted
- Guangxi University of Science and Technology, Liuzhou, China
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Dravet Syndrome (DS), a rare genetic encephalopathy characterized by severe drug-resistant epilepsy and progressive neurodevelopmental regression in infancy, is caused by de novo mutations in the SCN1A gene on chromosome 2q24 in over 80% of cases. This review synthesizes current insights into its molecular pathogenesis, precision diagnostics, and therapeutic innovations: SCN1A mutations disrupt Nav1.1 sodium channel expression and membrane trafficking in GABAergic interneurons through transcriptional dysregulation, pre-mRNA splicing defects, and gating dysfunction, thereby impairing inhibitory synaptic transmission and disrupting brainwide excitatory-inhibitory balance. Notably, polygenic interactions (e.g., DEPDC5, CHD2 variants), astrocytic calcium signaling aberrations, and mitochondrial metabolic deficits synergistically exacerbate network hyperexcitability. Diagnostic advancements include a stratified framework integrating early febrile seizure phenotypes, comprehensive SCN1A sequencing (including deep intronic variants), and multimodal assessments (e.g., γ-band EEG power analysis and hippocampal volumetry), which significantly accelerate clinical diagnosis and reduce misdiagnosis. Therapeutic strategies are evolving from empirical seizure control to mechanism-targeted interventions: antisense oligonucleotides (ASOs) restore SCN1A transcript integrity by blocking pathogenic exon inclusion; adeno-associated virus (AAV9)-mediated activation of GABAergic neuron-specific SCN1A promoters and CRISPR/dCas9-driven endogenous Nav1.1 upregulation have both been shown to improve inhibitory synaptic function and elevate seizure thresholds in preclinical models. Additionally, novel molecules such as the Nav1.1-selective agonist Hm1a and 5HT2BR receptor modulators offer new avenues by remodeling neuronal electrophysiology and neurotransmitter homeostasis. By dissecting the multi-dimensional molecular networks underlying DS and highlighting interdisciplinary integration of diagnostic-therapeutic technologies, this review provides a theoretical foundation for developing SCN1A-centric precision medicine, advocating a shift from symptomatic management to mechanism-driven interventions in clinical practice.
Keywords: Dravet syndrom, SCN1A, GABAergic, Antisence oligonucleotides, molecular
Received: 25 May 2025; Accepted: 25 Jun 2025.
Copyright: © 2025 Wang, Zhang, Huang, Wei, Wu and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jin Wang, Guangxi University of Science and Technology, Liuzhou, China
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