Dravet syndrome

Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI) typically presents in the first year of life, most often with prolonged, hemiclonic or generalised febrile seizures before 12 months of age in a previously healthy infant. Over the second year of life, multiple seizure types emerge, including focal, myoclonic, atypical absence, and atonic seizures, frequently triggered by fever, hyperthermia, illness, or visual stimuli. Seizures are characteristically drug-resistant, and prolonged episodes commonly progress to status epilepticus. Developmental trajectory is initially normal, followed by
stagnation and regression during the second year, with progressive intellectual disability, gait abnormalities, ataxia, and behavioural difficulties. Presentation and severity vary considerably between affected individuals, including within families carrying the same pathogenic variant. The condition carries an elevated risk of sudden unexpected death in epilepsy (SUDEP) and recurrent status epilepticus throughout life.

The estimated incidence is approximately 1 to 1 in 15,400 to 1 in 40,900 live births, based on pooled estimates from population-based studies in Europe and the United States.

Dravet syndrome is caused by germline pathogenic variants in several genes encoding ion channels and synaptic proteins. SCN1A accounts for approximately 80% of clinically diagnosed cases; rarer causes include PCDH19, SCN1B, GABRG2, and STXBP1. SCN1A encodes the alpha subunit (Nav1.1) of the neuronal voltage-gated sodium channel. Loss-of-function pathogenic variants predominantly impair the excitability of inhibitory GABAergic interneurons, resulting in cortical network hyperexcitability and the characteristic seizure phenotype. Both truncating and missense variants are reported, and a heterogeneous spectrum of pathogenic variants underlies disease.

Dravet syndrome is inherited in an autosomal dominant manner. Approximately 95% of probands carry a de novo pathogenic variant in SCN1A; only around 5% inherit the variant from a parent, who may be mildly affected or show somatic or germline mosaicism. The recurrence risk for siblings of a proband with a confirmed de novo variant is low but exceeds the general-population risk owing to the possibility of parental mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis is established according to the . Meeting these consensus criteria constitutes the clinical diagnosis of Dravet syndrome. Diagnosis is supported by the characteristic seizure semiology and developmental course. EEG is typically normal at onset; over time, generalised, focal, and multifocal epileptiform discharges may emerge. Brain MRI is usually normal at presentation and is performed mainly to exclude alternative structural causes. Molecular genetic testing of SCN1A, embedded in an epilepsy multigene panel, establishes the underlying genetic diagnosis.

Main differential diagnoses include:

• PCDH19 cluster epilepsy: phenotype can closely resemble Dravet syndrome; X-linked, with most symptomatic individuals being female; febrile and temperature-induced seizures occurring in clusters; PCDH19.
• : milder end of the SCN1A spectrum with febrile seizures persisting beyond age six and occasional afebrile seizures, typically without progressive encephalopathy or intellectual disability; SCN1A, SCN1B.
• SCN8A developmental and epileptic encephalopathy: intractable seizures with ataxic gait and occasional infantile spasms; often responsive to sodium-channel-blocker therapy, the opposite pharmacosensitivity to Dravet syndrome; SCN8A.

• Genetic testing establishes the molecular diagnosis, confirms the clinical suspicion, and ends the diagnostic odyssey for affected individuals and their families.
• Molecular confirmation enables specific and individualised surveillance and clinical management, including avoidance of contraindicated sodium-channel-blocking antiseizure medications and access to targeted therapies; decisions are made by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant allows predictive and reproductive testing of at-risk relatives and informs genetic counselling.

• Miller IO, Sotero de Menezes MA. SCN1A seizure disorders. 2007 Nov 29 [Updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301494.
• Strzelczyk A, Lagae L, Wilmshurst JM, Brunklaus A, Striano P, Rosenow F, et al. Dravet syndrome: a systematic literature review of the illness burden. Epilepsia Open. 2023;8(4):1256-70. doi:10.1002/epi4.12832. PMID:; PMCID: PMC10690674
• Zuberi SM, Wirrell E, Yozawitz E, Wilmshurst JM, Specchio N, Riney K, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1349-97. doi:10.1111/epi.17239. PMID:.
• Barcia G, Chemaly N, Gobin-Limballe S, Losito E, Aubart M, Sarda E, et al. Genetic etiologies with a large NGS panel in a monocentric cohort of 1000 patients with pediatric onset epilepsies. Epilepsia Open. 2025;10(4):1065-73. doi:10.1002/epi4.70057. PMID:; PMCID: PMC12362157