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

项目摘要/摘要 作为一名专注于癫痫遗传学的学术儿科神经学家，此次培训奖项的目标是扩大 奥尔森博士在研究罕见的早期遗传性癫痫的临床研究方法和基因分型方面所受的培训 表型相关。此外，它还旨在提高她的领导技能，专注于癫痫方面的知识 遗传学和CDKL5障碍，以及她发展和领导多学科研究合作的技能 用于翻译研究。培训将包括临床试验设计，以促进进入下一步 罕见疾病研究，她开发了一个独立的多学科研究计划，专注于CDKL5 精神障碍和其他罕见的遗传性癫痫。拟议的培训是在奥尔森博士之前在 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。这项工作将独特地将多学科的合作者网络聚集在一起，从而 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 问题。 Olson博士的主要导师Annapurna Poduri，医学博士，M.P.H.，我们癫痫遗传学项目的主任，将 在临床研究、基因-表型相关性、翻译方法以及 联合体科学。共同导师Tim Benke，M.D.，Ph.D.和Elizabeth Engle，M.D.各自添加独特 有CDKL5障碍和神经遗传学研究经验。这项工作将主要在 波士顿儿童医院和哈佛医学院。奥尔森博士领导着三个卓越中心之一 针对CDKL5障碍，并拥有当地、国家和国际优秀的临床和基础网络 科学合作者协助这项工作。 新生儿和婴儿发作的癫痫会导致严重的发病率和死亡率。有越来越多的人 确定了遗传病因。CDKL5障碍是一种公认的早期癫痫综合征，以 与特别难治性癫痫、一种严重的发育障碍、低眼压和大脑视觉有关 减损。稳健的表型特征和基因-表型相关性的评估 癫痫，包括CDKL5障碍，是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CDKL5的关键 无序。拟议的研究旨在1)确定CDKL5的预测因素和定义流行病学 障碍，2)建立CDKL5病的基因-表型相关性，以及3)评估 CDKL5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.