Mechanisms of Genetic Epilepsies

25.08.2016 bis 25.08.2016

Epilepsy is a common, severe and disabling condition with a major disease burden worldwide. Despite many available treatment options, the seizures are not well controlled in one third of all patients with epilepsy. Gene discovery and first functional analyses of genetic defects have been a major driver to unravel epileptogenic mechanisms in the last 20 years and have brought about the first personalized treatment options. However, most of the genetic alterations underlying epilepsy are still unknown and the development of novel treatment strategies for pharmacoresistant patients is largely hampered by our insufficient understanding of the underlying mechanisms. This project therefore aims to take research on genetic epilepsies to the next level by addressing (i) the ‘missing heritability’ of so far undetected genetic defects including both very rare mutations and complex inheritance patterns, (ii) the detailed mechanisms linking disease-relevant mutations to functional changes in neuronal networks that finally produce epileptic seizures in vivo, and (iii) the potential of the acquired knowledge to improve diagnostics and explore novel therapeutic possibilities.
The project will be focused on two genetically related epilepsy entities with a high heritability (>80%), which are not due to any structural brain lesions: (a) rare epileptic encephalopathies (EE), characterized by severe epilepsy of early childhood with developmental delay and intellectual disability (ID), and (b) common genetic (idiopathic) generalized epilepsies (GGE), including classical absence and other generalized epilepsy subtypes. We will use advanced technologies ranging from new analysis tools applied to the largest genome-wide datasets worldwide (approximately 7000 GWAS and 6000 whole exome datasets from GGE patients, and >2000 whole exome datasets of EE patient-parent trios) to unprecedented in situ and in vivo studies to unravel the complex dysfunction of neuronal networks in genetic animal models using optogenetic manipulation and 2-photon imaging. This approach is supposed to not only identify a large number of further epilepsy genes but enable the link from genetic findings to a deeper understanding of their pathophysiology, and identification of a limited number of distinct disease pathways with respective appropriate treatment options.
Most of the involved groups and external partners know each other well from previous collaborations so that this project builds on existing common infrastructures, including data repositories, analysis tools and genetic animal models. The proposed project will capitalize on this structural framework and develop new exciting connections between the research groups. All groups will be tightly linked by using a common pool of data, models and techniques and working collaboratively on the same aforementioned goals. The Research Unit will be unique in its composition linking high-end genetics and physiological studies from molecules to systems, and from gene to function and therapy. Concerning its international standing, the unit will consolidate a crucial German and Luxembourg contribution to epilepsy genetics and mechanisms worldwide. We will foster exchange of knowledge and personnel between internal groups and with external partners and develop specific elements of graduate training attached to existing graduate schools in our centres, so that we anticipate a significant added value for this Research Unit from both a scientific and a structural long-term perspective.