Biallelic SCN1A variants with divergent epilepsy phenotypes

Abstract

Purpose: Pathogenic SCN1A variants most commonly cause autosomal dominant Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+). However, rare homozygous SCN1A variants have also been reported. We report two new cases of homozygous SCN1A variants associated with divergent epilepsy phenotypes.

Methods: We retrospectively reviewed the charts of two unrelated patients with different homozygous SCN1A variants. We also reviewed all published cases of biallelic SCN1A pathogenic variants, focusing on the epilepsy phenotypes.

Results: Patient 1 had a homozygous c. 1676T>A, (p. Ile559Asn) variant of uncertain significance, inherited from asymptomatic parents. Patient 1 exhibited early afebrile seizures controlled by first-line anti-seizure medications and no febrile seizures or status epilepticus, as well as profound developmental delay, macrocephaly, and mild dysmorphic features. Patient 2 had a homozygous pathogenic c. 4970G>A, (p. Arg1657His) variant carried by asymptomatic parents. This patient presented with early, recurrent, and prolonged febrile seizures, moderate developmental delay, and motor dysfunction and was diagnosed with Dravet syndrome. We identified 16 further cases from the literature. Including our cases, 9/18 (50 %) were diagnosed with Dravet syndrome and 6/18 (33 %) with GEFS+. The mean age of seizure onset was 7 months (range 3-19 months). Phenotypes ranged from intact neurodevelopment with controlled epilepsy to profound developmental delay and refractory epilepsy.

Conclusion: These cases highlight and expand the phenotypic spectrum associated with biallelic SCN1A variants. While some patients present typically for Dravet/GEFS+, others may present with developmental delay in the absence of febrile seizures or status epilepticus. Further studies are needed to confirm genotype-phenotype relationships.

Keywords: Autosomal Recessive; Developmental and epileptic encephalopathy; Dravet syndrome; Epilepsy; Genetic epilepsy with febrile seizures plus (GEFS+); Homozygous; SCN1A.