Pathophysioloy of non-classic epileptic encephalopathies (EE)

• Applicants: Professor Dr. Ingo Helbig; Professorin Dr. Yvonne Weber
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262469906

Epileptic encephalopathies (EE) are individually rare but collectively common disorders of the central nervous system (CNS). EE are severe, intractable epilepsies that usually start in childhood and are associated with a poor cognitive outcome. While epileptic encephalopathies can occur as the result of identifiable lesions in the CNS such as malformations, a causative factor cannot be identified in a broad subset of cases. Genetic factors are implicated, but until recently, the discovery of the underlying genetic alterations turned out to be elusive. With the advent of high-throughput sequencing technologies, a genetic basis could be identified for the classic epileptic encephalopathies including Infantile Spasms (IS) and the Lennox-Gastaut syndrome (LGS). De novo mutations were found to contribute significantly to the etiology of these conditions and large, collaborative studies are currently performed to increase the fractions of cases explained in IS and LGS. In these international studies, the applicants are already taking a leading role as project leaders and coordinators. In the current proposal, we aim to expand our gene-identification strategy to a broader range of EE such as the non-classical forms which cannot be classified into the traditional syndromes. These EE, which pose a major diagnostic and therapeutic challenge in clinical practice, have not been included in systematic studies so far. There is strong evidence that de novo mutations play a large role in these conditions, which are clinically highly relevant and currently without sufficient treatment options. We aim to identify de novo mutations using trio exome sequencing in 100 patient-parent trios with follow-up analysis in 500 patients using a gene panel analysis of the 50 most promising candidate genes. We will perform functional analysis in the 5 most promising proteins. Given the absence of comparable projects on a national and European scale, this study will provide the necessary foundation to launch future confirmation and functional studies on a broad range of so far neglected EE. This current proposal application is a resubmission of a previous proposal by the applicants in December 2012. We believe that we fully address the comments and suggestions of the reviewers and of the DFG panel. In addition, we put out proposal in context to (1) recent developments in the field that change some aspects of this application and (2) progress in the expertise of the applicants particularly with respect to next-generation sequencing technologies. We also address the importance of the application in the context of overall competition and funding landscape in this area, as this proposal will allow the applicants to establish their role as leaders in the field.

• DFG Programme: Research Grants