SCN1A – Lennox-Gastaut Syndrome

Heterozygous mutations in SCN1A, encoding the neuronal NaV1.1 sodium channel, are well established in Dravet syndrome and other epileptic encephalopathies and have also been reported in rare cases of Lennox-Gastaut syndrome (LGS). In a cohort of 22 adult patients with LGS features, a single splice‐donor variant, c.383+1A>G, was identified, demonstrating clinical overlap between LGS and Dravet syndrome (PMID:19782004). In contrast, a retrospective study of alleged vaccine-associated encephalopathy found no SCN1A mutations in the subset of patients classified as LGS (PMID:16713920). Together, these data provide limited genetic evidence for SCN1A in LGS.

Functional analyses of diverse SCN1A variants reveal a consistent loss-of-function mechanism. Mouse knock-in models of the recurrent R1648H mutation show impaired GABAergic interneuron firing and reduced inhibition, supporting haploinsufficiency (PMID:20100831). Studies of truncating SCN1A alleles confirm pure haploinsufficiency without dominant-negative effects (PMID:22150645). While these findings establish a coherent pathogenic mechanism, direct functional characterization of LGS‐associated variants remains lacking. Key Take-home: SCN1A testing should be considered in unexplained LGS cases, although pathogenic variants appear rare.

References

• Epilepsy & behavior : E&B • 2009 • SCN1A mutation screening in adult patients with Lennox-Gastaut syndrome features. PMID:19782004
• The Lancet. Neurology • 2006 • De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. PMID:16713920
• The Journal of biological chemistry • 2010 • Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities. PMID:20100831
• Epilepsia • 2012 • Pure haploinsufficiency for Dravet syndrome Na(V)1.1 (SCN1A) sodium channel truncating mutations. PMID:22150645

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