Determinants of variable disease severity in SCN1A-related phenotypes and X-chromosomal epilepsy syndromes

Dravet syndrome Dravet syndrome is one of the most well-known genetic epilepsy syndromes. The main characteristics of the disease are early onset intractable epileptic seizures in the first year of life, accompanied by a delayed psychomotor development in the second year of life, resulting in mild to severe intellectual disability in most patients. Mutations in one of both copies of the SCN1A-gene are the cause of disease in the majority of Dravet syndrome patients. Phenotypic variability Pathogenic variants in SCN1A can give rise to not only Dravet syndrome, but also to milder phenotypes, such as genetic epilepsy with febrile seizures plus (GEFS+), febrile seizures plus (FS+) and febrile seizures. This discrepancy can be partly explained by the different mutation types that are associated with the respective disorders. This however does not explain all differences between patients with SCN1A-related epilepsy: patients with similar mutations may show a wide phenotypic variability and even the exact same SCN1A mutation does not always result in the same phenotype. For parents of young patients, it is understandably very important to accurately predict the clinical course after a pathogenic SCN1A variant has been detected. In this thesis, we have investigated several potential modifiers that may influence clinical outcomes of genetic epilepsy syndromes, to ultimately improve counseling of patients and/or parents. Influence of modifiers We conclude that many different modifiers influence the severity of SCN1A-related disease. Examples are modifier genes, variants in regulatory regions of the SCN1A-gene, medication use and mosaicism. Mosaicism does not only influence the severity of SCN1A-related phenotypes, but also that of two X-linked epilepsy syndromes we have researched (PCDH19- and KIAA2022-related epilepsy). We can investigate several of these modifiers in individual patients already. When detection of mosaicism is implemented in regular diagnostics, parents can be better informed regarding the expected severity of the disease and the recurrence risk for future children. We also show that the age at which a first afebrile seizure occurs is a good predictor for disease severity. We furthermore show that the prolonged use of contra-indicated medication has a negative effect on mental development. We therefore conclude that it is of great importance to detect SCN1A pathogenic variants at a young age, before maintenance treatment is initiated and contra-indicated medication can be avoided.