Not all <i>SCN1A</i> epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.

Abstract

To define a distinct <i>SCN1A</i> developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and <i>SCN1A</i> mutation. 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 <i>SCN1A</i> 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. Here, we present a phenotype-genotype correlation for <i>SCN1A</i>. We describe a distinct <i>SCN1A</i> phenotype, early infantile <i>SCN1A</i> 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.