Febrile Seizures (Second Edition) - Chapter 3: SCN1A and Dravet syndrome

Elsevier, Febrile Seizures (Second Edition) New Concepts and Consequences 2023, Pages 43-63
Richard E.Rosch and Ethan M.Goldberg

Dravet syndrome (DS) is a severe neurodevelopmental disorder largely due to heterozygous pathogenic variants in SCN1A encoding the voltage-gated sodium channel α-subunit NaV1.1. DS is clinically defined by normal early childhood development followed by infantile onset of recurrent and prolonged seizures with prominent temperature sensitivity, as well as developmental delay, autism spectrum disorder, behavioral dysfunction, ataxia, and increased mortality. As the most temperature-sensitive form of epilepsy, the study of DS may enlighten our understanding of the mechanisms of febrile seizures more generally. The majority of DS-associated variants in SCN1A exert a loss of function effect on NaV1.1-containing sodium channels, which are critical for the generation and propagation of action potentials. NaV1.1 is preferentially expressed in GABAergic inhibitory interneurons throughout the brain, and specific subsets of interneurons are dysfunctional in DS, which may lead to a net impairment of synaptic inhibition as the pathomechanism underlying epilepsy in this syndrome. Extensive research on basic mechanisms of DS over the last 20 years has provided important insights informing basic mechanisms underlying febrile seizures in general.