Diagnosis and genotype-phenotype correlations in early life epilepsy and CDKL5 disorder

作为一名专注于癫痫遗传学的儿科神经科学术专家，该培训奖的目标是扩大Olson博士在研究罕见的早期遗传性癫痫和基因-表型相关性的临床研究方法方面的培训。此外，它旨在提高她的领导技能，专注于癫痫遗传学和CDKL5障碍的知识，以及她为翻译研究开发和领导多学科研究合作的技能。培训将包括临床试验设计，以促进罕见疾病研究的下一步，因为她开发了一个独立的多学科研究计划，专注于CDKL5障碍和其他罕见遗传性癫痫。拟议的培训扩大了奥尔森博士先前在癫痫和神经遗传学方面的培训，研究经验，包括NSADA奖，以及临床研究和流行病学培训。这项工作将独特地将多学科合作者网络聚集在一起，使基础科学影响临床护理，使临床研究将基础科学研究集中在与临床相关的问题上。Olson博士的主要导师Annapurna Poduri，M.D.，M.P.H.是我们癫痫遗传学项目的主任，他将在临床研究、基因-表型相关性、翻译方法和联盟科学方面提供指导。共同导师Tim Benke，M.D.，Ph.D.和Elizabeth Engle，M.D.分别在CDKL5障碍和神经遗传学研究方面增加了独特的经验。这项工作将主要在波士顿儿童医院和哈佛医学院进行。奥尔森博士是CDKL5障碍三个卓越中心之一的负责人，并可以接触到由优秀的临床和基础科学合作者组成的地方、国家和国际网络来协助这项工作。新生儿和婴儿发作的癫痫会导致严重的发病率和死亡率。越来越多的人发现了遗传病因。CDKL5障碍是一种公认的早期癫痫综合征，尤其与难治性癫痫、一种严重的发育障碍、低眼压和脑视力障碍有关。包括CDKL5障碍在内的遗传性癫痫的强健表型特征和基因-表型相关性的评估是迈向合理精确治疗的一步。鉴于CDKL5的难治性，科学地理解和治疗CDKL5疾病将是至关重要的。这项拟议的研究旨在1)确定CDKL5疾病的预测因素并确定流行病学，2)建立CDKL5疾病的基因-表型相关性，以及3)评估CDKL5相关癫痫痉挛对标准治疗的反应。

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.