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

早期癫痫和 CDKL5 疾病的诊断和基因型-表型相关性

基本信息

批准号：
10377934
负责人：
Heather Elisa Olson
金额：
$ 19.82万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377934
关键词：
Address Age Award Basic Science Boston Brain CDKL5 disorder Categories Child Childhood Clinic Clinical Clinical Research Clinical Sciences Clinical Trials Clinical Trials Design Cohort Analysis Collaborations Complement Control Groups Cyclin-Dependent Kinases Data Databases Development Development Plans Diagnosis Disease Doctor of Medicine Electroencephalography Electrophysiology (science)Epidemiology Epilepsy Etiology Evaluation Future Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genotype Goals Hormonal Incidence Infant Infantile spasms Intellectual functioning disability Interdisciplinary Study International Intractable Epilepsy Knowledge Lead Leadership Learning Life Master of Public Health Medical Mendelian disorder Mentors Methodology Morbidity - disease rate Muscle hypotonia Natural History Nature Neonatal Neurologist Observational Study Pathogenicity Patients Pediatric Hospitals Phase Phenotype Phosphotransferases Pilot Projects Population Precision therapeutics Prognosis Proteins Rare Diseases Refractory Regression Analysis Research Research Design Research Training Science Seizures Severities Spasm Synapses Syndrome Techniques Testing Training Translational Research Variant Vigabatrin Visual evoked cortical potential Vulnerable Populations Work base career development childhood epilepsy clinical biomarkers clinical care clinical diagnosis clinical epidemiology clinical predictors clinically relevant cohort cortical visual impairment design developmental disease exome sequencing experience gene panel genetic disorder diagnosis genetic variant improved infancy ketogenic diet medical schools mortality multidisciplinary neurogenetics next generation sequencing novel diagnostics phenotypic data programs recruit research study response skills standard care targeted treatment translational approach

项目摘要

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.

作为一名专注于癫痫遗传学的学术儿科神经科医生，该培训奖的目标是扩大奥尔森博士在临床研究方法中的培训，以研究罕见的早期生命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，集中在癫痫遗传学和CDKL5障碍方面的知识，以及她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，以促进稀有疾病研究的下一步发展，因为她开发了一项针对CDKL5疾病和其他罕见遗传性癫痫的独立多学科研究计划。拟议的培训扩展了Olson博士先前在癫痫和神经源性方面的培训，包括NSADA奖在内的研究经验以及临床研究和流行病学的培训。这项工作将独特地汇集一个由合作者组成的多学科网络，从而使基础科学能够影响临床护理和临床研究，从而将基础科学研究集中在临床上相关的问题上。 Olson博士的主要导师Annapurna Poduri，医学博士，M.P.H.，我们的癫痫遗传学计划主任，将在临床研究，基因型 - 表型相关性，转化方法和财团科学方面提供指导。蒂姆·贝克（Tim Benke，M.D.这项工作将主要在波士顿儿童医院和哈佛医学院完成。 Olson博士指示CDKL5障碍卓越卓越中心之一，并可以使用优秀的临床和基础科学合作者的本地，国家和国际网络来协助这项工作。新生儿和婴儿发作癫痫会导致明显的发病率和死亡率。越来越多的遗传病因。 CDKL5疾病是一种已建立的早期癫痫综合征，以特别是与难治性癫痫，严重的发育障碍，性低下和脑视觉障碍相关的疾病。需要强大的表型表征和评估遗传性癫痫（包括CDKL5疾病）的基因型 - 表型相关性，作为迈向理性精确治疗的一步。鉴于其难治性，科学驱动的理解和治疗方法在CDKL5疾病中至关重要。提出的研究目的是1）确定预测因子并定义CDKL5疾病的流行病学，2）在CDKL5疾病中建立基因型 - 表型相关性，以及3）评估CDKL5相关的癫痫痉挛对标准处理的反应。