Abstracts

Summary: Until now, the discovery of genes for monogenic epilepsies has not had significant clinical impact. With the finding that around 70% of children with Dravet syndrome, or severe myoclonic epilepsy of infancy, have mutations of SCN1A, epilepsy genetics has moved into the clinical domain. Recognition of Dravet syndrome requires an understanding of a complex phenotype including seizure onset in the first year of life, multiple seizure types, developmental slowing, neurological deficits and EEG features. Genotype-phenotype correlation has led to the identification of novel SCN1A epileptic encephalopathies such as severe infantile multifocal epilepsy that should also be considered for mutational analysis. Translational research with the development of animal models of SCN1A mutations has led to significant insights into the neurobiology of Dravet syndrome. SCN1A knockout mice recapitulate the human disorder with seizures and ataxia leading to early death in heterozygotes. Mice show strain-specific penetrance of disease reflecting the genetic background effects that modify phenotypic severity in humans. Cellular studies show that dysfunction of the interneuron in cortex, rather than excitatory cells, underlies the phenotype. GABAergic cells are also implicated in the cerebellum with Purkinje cell dysfunction underlying ataxia. The diagnostic finding of a SCN1A mutation associated with Dravet syndrome or a related phenotype has major implications for treatment, prognostic and genetic counseling. Specific antiepileptic agents are effective in Dravet syndrome whilst others cause seizure exacerbation. Stiripentol has been shown to be effective in Dravet syndrome. Early diagnosis allows the clinician to optimise anti-epileptic therapy with the aim of improving developmental outcome.