Clinical and Genetic Features of Dravet Syndrome: A Prime Example of the Role of Precision Medicine in Genetic Epilepsy

Abstract

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.

Keywords: developmental epileptic encephalopathy; dravet syndrome; epilepsy syndrome; genetics; targeted therapy.

Figure 2

The typical structure of a voltage-gated Nav channel. (A) The VGSC contains α and β subunits, which are transmembrane proteins. The α subunit contains four homologous domains (DI-IV). Each domain comprises six transmembrane regions (S1–S6). S1–S4 forms the voltage-sensing domain, and S5 and S6 comprise the pore-forming domain. The β subunits have a single transmembrane segment, a short intracellular domain with a single loop. (B) Top view from the extracellular face and side view of the Nav channel. The four domains of the α subunit form a Na⁺ permeable pore lined by the re-entrant S5–S6 pore-loop segments. (C) The location of some SCN1A variants, which are summarized from three studies [47,116,117].

Figure 1

Comorbidities in individuals with DS. TSH: thyroid-stimulating hormone; IGF-1: insulin-like growth factor 1; SUDEP: sudden unexpected death in epilepsy.