Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype

Abstract

Objective: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.

Methods: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.

Results: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.

Conclusions: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

Figure. MRI in children with early infantile SCN1A encephalopathy

(A–C) Coronal views in case 1 (3 years of age), case 9 (5 years of age), and case 2 (1 year of age) show bilateral small hippocampi. (A) Case 1 developed left hippocampal sclerosis. (C) Case 2 has a malrotated left hippocampus. (D, F) Axial T2 and coronal T1 images of case 9 show (D) normal white matter volume at 2 months of age with (F) moderately severe volume loss at 2 years. (E) Coronal views of the hippocampi at 2 months show bilateral small hippocampi with left hippocampal malrotation.