LAUSR

SCN1A, long referred to as the most important epilepsy gene, continues to deliver exciting scientific surprises. It has always been associated with a broad phenotypic spectrum ranging from developmental and epileptic encephalopathies (DEEs), with Dravet syndrome being the prototypic and most frequent form, to selflimited, pharmacoresponsive phenotypes within the GEFS+ (Genetic Epilepsy with Febrile Seizures Plus) spectrum.1,2 These disorders are due to lossoffunction (LoF) pathogenic variants. In 2017, we described the far more profound Early Infantile DEE (EIDEE) due to SCN1A pathogenic missense variants, associated with a hyperkinetic movement disorder.3 Onset was in the first 3 months of life and included seizure types not seen in Dravet syndrome, such as epileptic spasms. Our original seven patients included six with the recurrent missense pathogenic variant, T226M. We postulated that SCN1AEIDEE was due to gain of function (GoF) of the sodium channel, given its phenotypic similarity to SCN2AEIDEE and SCN8AEIDEE, a hypothesis later proven with elegant dynamic action patch clamping studies.4 Increasing recognition of the spectrum of SCN1A GoF disorders, and epilepsies in particular, has occurred in the past few months. Brunklaus and colleagues extended the GoF phenotypic spectrum to include neonatal onset DEE, falling within the onset period of EIDEE.5 The International League Against Epilepsy definition for infants with onset of a DEE under 3 months is now "early infantile" rather than "early onset," as the latter term is often used imprecisely to encompass many ages of onset.6 The extended spectrum of SCN1A GoF epilepsies included babies with arthrogryposis, including some who died in utero with arthrogryposis on antenatal studies.5 In this issue, two studies add to the emerging spectrum of SCN1A GoF epilepsies, with functional studies deepening our understanding of the physiological consequences and highlighting critical therapeutic implications. Marticardi and coauthors describe the widening GoF spectrum, confirming the EIDEE phenotypes and bringing novel insights to the milder end of the SCN1A GoF epilepsies.7 They report patients with focal epilepsies beginning in infancy or childhood, at a median of 7.5 years, in the setting of normal intellect or mild impairment. These focal epilepsies are often inherited, and febrile seizures are not prominent. The recurrent SCN1A p.R1636Q pathogenic variant has now been identified in 12 individuals, including four reported by Clatot and coauthors.8 They show mixed gain and loss of function changes on physiological studies, resulting in an overall moderate GoF. Identical variants in paralogous sodium channel subunit genes show similar functional effects, underlining the supportive information that can be gleaned from functional studies in related genes. There remains a significant disparity between the severity in GoF and phenotypic outcome. Matricardi et al. demonstrate a more severe GoF across a range of biophysical parameters in the SCN1A variants causing EIDEE compared with those associated with infantile and childhood focal epilepsies.7 However, the epilepsies present a