The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation-positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment.
We screened for PCDH19 mutations in 75 girls diagnosed with Dravet syndrome (DS) without a SCN1A mutation and 29 girls with fever-sensitive and cluster seizures.
Heterozygous Scn1a knockout (Scn1a <sup>+/-</sup>) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model.
Mutations in the SCN1A gene causing either loss or gain of function have been frequently found in patients affected by genetic epilepsy with febrile seizures plus (GEFS+) or Dravet syndrome (also named severe myoclonic epilepsy in infancySMEI).
It has been established that febrile seizures and its extended syndromes like generalized epilepsy with febrile seizures (FS) plus (GEFS+) and Dravet syndrome have been associated with mutations especially in SCN1A and GABRG2 genes.
Our study expands the spectrum of known SCN1A variants and confirms the current understanding of the role of the genetic background and epilepsy severity in determining the developmental outcome of Dravet syndrome patients.
The frequency of pathogenic variants was 4.17% in all the patients and 11.1% in DS patients, which, together with other publications, emphasize that specific and more severe phenotypes are associated with SCN1A mutations.
Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic-clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy.
We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically.
All identified variants were found in DS patients with 85.7% sensitivity, thus supporting the role of profound SCN1A gene variants in etiology of DS phenotype.
Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry.
Since SCN1A is expressed in the motor neuron initial segment, we explored whether motor neuron dysfunction could contribute to gait disturbance and orthopedic misalignment in patients with Dravet syndrome due to SCN1A mutations.
In Dravet syndrome (DS), a mutation in SCN1A, coding for the voltage-gated sodium channel Nav1.1, is associated with severe cognitive impairment and seizures.