Pathophysiology of epileptic encephalopathies: insights from genetics in patients and in vivo modelling in zebrafish and fruit flies.

We aim to perform genomic analyses to unravel the genetics of epileptic encephalopathies (EE) and to subsequently functionally investigate novel proteins/pathways implicated in the development of these severe disorders. Using whole exome sequencing in sib pairs affected with EE we envisage identifying multiple interesting variants of unknown significance in a broad set of genes. In a preliminary WES study we have already identified one such interesting group of genes , namely the aminoacyl-tRNA synthesases. To find proof of a link between these and other interesting candidate genes and EE, in a first step we aim to screen 500 EE patients by gene panel analysis to identify mutations in multiple unrelated patients providing additional genetic evidence. Secondly, we will model a deficiency of these novel genes implicated in EE in zebrafish, and look for evidence of an epilepsy phenotype. Next, we aim to elucidate the pathomechanism more precisely by investigating the cell biology in mutagenized animal models like fruit fly, using complementary methodologies such as transcriptomics, electrophysiology, immunohistochemistry, live imaging and electron microscopy. This in vivo functional validation will help us to understand the pathophysiology of EE, and additionally will form a starting point for pharmacological studies, which may uncover potential therapeutic strategies for improved seizure control.