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

项目概要/摘要 作为一名专注于癫痫遗传学的学术儿科神经学家，这项培训奖的目标是扩大 博士Olson在研究罕见的早期遗传性癫痫和基因型的临床研究方法方面的培训- 表型相关此外，它旨在提高她的领导技能，专注于癫痫知识 遗传学和CDKL 5疾病以及她的技能，以发展和领导多学科研究合作 用于转化研究。培训将包括临床试验设计，以促进进入下一阶段， 罕见疾病研究，她开发了一个独立的多学科研究计划，重点是CDKL 5 和其他罕见的遗传性癫痫。拟议的培训扩大了奥尔森博士以前的培训， 癫痫和神经遗传学，研究经验，包括NSADA奖，以及临床研究培训 和流行病学。这项工作将独特地汇集多学科合作者网络， 基础科学影响临床护理和临床研究，将基础科学研究集中在临床相关领域 问题. 博士奥尔森的主要导师安娜普纳·波杜里，医学博士，M.P.H.我们癫痫遗传学项目的负责人威尔 在临床研究、基因型-表型相关性、转化方法方面提供指导， 财团科学共同导师蒂姆·本克，医学博士，博士和Elizabeth Engle，M.D.每个添加唯一 分别在CDKL 5紊乱和神经遗传学研究方面有丰富的经验。这项工作将主要在 波士顿儿童医院和哈佛医学院。奥尔森博士指导三个卓越中心之一 CDKL 5障碍，并有机会获得当地，国家和国际网络的优秀临床和基础 科学合作者协助这项工作。 新生儿和婴儿癫痫发作导致显著的发病率和死亡率。存在着日益 确定了遗传病因。CDKL 5障碍是一种已确定的早期癫痫综合征， 与特别难治性癫痫、严重发育障碍、张力减退和大脑视觉障碍相关 损伤基因型-表型相关性的稳健表型表征和评估 癫痫，包括CDKL 5紊乱，需要作为迈向合理精确治疗的一步。鉴于其 难治性，科学驱动的理解和治疗方法将是至关重要的CDKL 5 disorder.拟议的研究旨在1）确定CDKL的预测因子并定义其流行病学5 疾病，2）建立CDKL 5疾病的基因型-表型相关性，和3）评估 CDKL 5相关癫痫痉挛的标准治疗。

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.