SCN1A – Dravet syndrome

Severe myoclonic epilepsy in infancy (Dravet syndrome) is a catastrophic infantile-onset epileptic encephalopathy characterized by prolonged febrile and afebrile seizures, developmental delay, cognitive regression, and high risk of status epilepticus. Heterozygous pathogenic variants in the voltage-gated sodium channel gene SCN1A are identified in the vast majority of patients, most arising de novo, with occasional familial inheritance and parental mosaicism (PMID:16122630, PMID:19673951).

1. Clinical Validity

Inheritance is autosomal dominant with ~80% de novo variants and rare parental mosaic cases. Over 240 unrelated probands with SCN1A variants have been reported in Dravet syndrome cohorts (PMID:12083760, PMID:23195492). Additional affected relatives (n = 4) segregate pathogenic variants, including siblings and half-sisters (PMID:16122630).

2. Genetic Evidence (Strong)

SCN1A variant spectrum comprises two-thirds truncating mutations (nonsense/frameshift) and one-third missense mutations (PMID:16122630). Over 250 distinct pathogenic variants have been cataloged, including splice-site and in-frame changes (PMID:23195492). Representative variant: c.5138G>A (p.Ser1713Asn).

3. Functional Evidence (Strong)

Patch-clamp studies in heterologous cells show complete loss-of-function for truncating and many missense mutants (PMID:12837571), while select variants exhibit impaired fast inactivation and increased persistent current (PMID:15263074). A mouse knock-in model of the GEFS+ allele R1648H recapitulates seizures and GABAergic interneuron dysfunction (PMID:20100831).

4. Mechanism and Modifiers

Haploinsufficiency of NaV1.1 disrupts inhibitory interneuron firing, lowering seizure threshold. Phenotypic variability arises from genetic modifiers, mosaicism, and differential variant effects on channel gating.

Key Take-home

SCN1A testing is essential for early diagnosis of Dravet syndrome, guiding therapy selection and genetic counseling.

References

• Biochemical and biophysical research communications • 2002 • Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy PMID:12083760
• Brain & development • 2005 • A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures PMID:16122630
• Clinical genetics • 2009 • Parental SCN1A mutation mosaicism in familial Dravet syndrome. PMID:19673951
• Epilepsy research • 2012 • Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy. PMID:23195492
• Epilepsia • 2003 • Nav1.1 channels with mutations of severe myoclonic epilepsy in infancy display attenuated currents. PMID:12837571
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy. PMID:15263074
• The Journal of biological chemistry • 2010 • Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic interneuron abnormalities. PMID:20100831

Evidence Based Scoring (AI generated)