Diagnosis and Genotype-Phenotype Correlations in Early Life Epilepsy and CDKL5 Disorder

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PROJECT SUMMARY/ABSTRACT As an academic pediatric neurologist focusing on epilepsy genetics, the goal of this training award is to expand Dr. Olson's training in clinical research approaches for study of rare early life genetic epilepsies and genotype- phenotype correlations. Further it aims to advance her leadership skills, focused knowledge in epilepsy genetics and CDKL5 disorder as well as her skills to develop and lead multidisciplinary research collaborations for translational research. Training will include clinical trials design to facilitate advancement to next steps in rare disease research as she develops an independent multidisciplinary research program focused on CDKL5 disorder and other rare genetic epilepsies. The proposed training expands on Dr. Olson's prior training in epilepsy and neurogenetics, research experience including an NSADA award, and training in clinical research and epidemiology. This work will uniquely bring together a multidisciplinary network of collaborators, allowing basic science to impact clinical care and clinical research to focus basic science research on clinically relevant questions. Dr. Olson's primary mentor Annapurna Poduri, M.D., M.P.H., Director of our Epilepsy Genetics Program, will provide guidance in clinical research, genotype-phenotype correlations, translational approaches, and consortium science. Co-mentors Tim Benke, M.D., Ph.D and Elizabeth Engle, M.D. each add unique experience in CDKL5 disorder and neurogenetics research, respectively. The work will be done primarily at Boston Children's Hospital and Harvard Medical School. Dr. Olson directs one of three Centers of Excellence for CDKL5 disorder, and has access to a local, national and international network of excellent clinical and basic science collaborators to assist in this work. Neonatal and infantile onset epilepsy results in significant morbidity and mortality. There are increasingly identified genetic etiologies. CDKL5 disorder is one established early life epilepsy syndrome notable for being associated with particularly refractory epilepsy, a severe developmental disorder, hypotonia and cerebral visual impairment. Robust phenotype characterization and assessment of genotype-phenotype correlations of genetic epilepsies, including CDKL5 disorder, is needed as a step towards rational precision therapy. Given its refractory nature, a scientifically driven approach to understanding and treatment will be critical in CDKL5 disorder. The proposed research study aims to 1) determine predictors and define epidemiology of CDKL5 disorder, 2) establish genotype-phenotype correlations in CDKL5 disease, and 3) evaluate response of CDKL5-associated epileptic spasms to standard treatments.