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学术儿科神经学家，该培训奖项的目标是扩大奥尔森博士在临床研究方法方面的培训，以研究罕见的早期遗传性癫痫和基因型-表型相关性。此外，它旨在提高她的领导能力，在癫痫遗传学和CDKL 5疾病的重点知识，以及她的技能，开发和领导多学科研究合作的转化研究。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，重点是CDKL 5疾病和其他罕见的遗传性癫痫。拟议的培训扩展了奥尔森博士先前在癫痫和神经遗传学方面的培训，包括NSADA奖在内的研究经验，以及临床研究和流行病学方面的培训。这项工作将独特地汇集多学科合作者网络，使基础科学能够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上。奥尔森博士的主要导师安娜普纳·波杜里，医学博士，M.P.H.我们的癫痫遗传学项目主任，将提供临床研究，基因型-表型相关性，翻译方法和联盟科学的指导。共同导师蒂姆·本克，医学博士，博士和Elizabeth Engle，M.D.每个人都分别在CDKL 5疾病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。Olson博士领导着CDKL 5疾病的三个卓越中心之一，并有机会获得当地，国家和国际优秀临床和基础科学合作者网络，以协助这项工作。新生儿和婴儿癫痫发作导致显著的发病率和死亡率。有越来越多的确定遗传病因。CDKL 5障碍是一种确定的早期癫痫综合征，其显著特征在于与特别难治性癫痫、严重发育障碍、张力减退和脑视觉障碍相关。遗传性癫痫（包括CDKL 5疾病）的基因型-表型相关性的稳健表型表征和评估是迈向合理精确治疗的一步。鉴于其难治性，科学驱动的方法来理解和治疗CDKL 5疾病将是至关重要的。这项研究的目的是：1）确定CDKL 5疾病的预测因子和流行病学定义，2）建立CDKL 5疾病的基因型-表型相关性，3）评估CDKL 5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.