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：
10758725
负责人：
Heather Elisa Olson
金额：
$ 23.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758725
关键词：
Award Basic Science Boston CDKL5 disorder Child Childhood Clinical Research Clinical Sciences Clinical Trials Clinical Trials Design Collaborations Development Diagnosis Disease Doctor of Medicine Epidemiology Epilepsy Genetic Genetic Diseases Genetic Predisposition to Disease Genotype Goals Interdisciplinary Study International Intractable Epilepsy Knowledge Lead Leadership Life Master of Public Health Medical Mentors Morbidity - disease rate Muscle hypotonia Nature Neonatal Neurologist Pediatric Hospitals Phenotype Precision therapeutics Prognosis Rare Diseases Refractory Research Science Spasm Syndrome Training Translational Research Vulnerable Populations Work clinical care clinical diagnosis clinical epidemiology clinically relevant cortical visual impairment design developmental disease experience infancy medical schools mortality multidisciplinary neurogenetics programs research study response skills standard care targeted treatment translational approach

项目摘要

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.

项目概要/摘要作为专注于癫痫遗传学的学术儿科神经学家，该培训奖的目标是扩大奥尔森博士在罕见的早期生命遗传性癫痫和基因型研究的临床研究方法方面接受过培训- 表型相关性。此外，它还旨在提高她的领导技能和癫痫方面的重点知识遗传学和 CDKL5 疾病以及她发展和领导多学科研究合作的技能用于转化研究。培训将包括临床试验设计，以促进下一步的进展她开发了一个专注于 CDKL5 的独立多学科研究项目，致力于罕见疾病研究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之前的培训癫痫和神经遗传学、研究经验（包括 NSADA 奖项）以及临床研究培训和流行病学。这项工作将以独特的方式汇集多学科合作者网络，使基础科学影响临床护理和临床研究，将基础科学研究重点放在临床相关方面问题。 Olson 博士的主要导师 Annapurna Poduri，医学博士，公共卫生硕士，我们癫痫遗传学项目的主任，将提供临床研究、基因型-表型相关性、转化方法等方面的指导联盟科学。共同导师蒂姆·本克 (Tim Benke) 医学博士、哲学博士和伊丽莎白·恩格尔 (Elizabeth Engle) 医学博士各自添加了独特的内容分别在 CDKL5 疾病和神经遗传学研究方面拥有经验。这项工作将主要在波士顿儿童医院和哈佛医学院。奥尔森博士领导三个卓越中心之一用于 CDKL5 疾病，并可以访问当地、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导致显着的发病率和死亡率。有越来越多的确定了遗传病因。 CDKL5 疾病是一种已确定的生命早期癫痫综合征，因其与特别难治性癫痫、严重发育障碍、肌张力低下和脑视觉有关损害。遗传的基因型-表型相关性的稳健表型表征和评估癫痫，包括 CDKL5 疾病，需要作为合理精准治疗的一步。鉴于其难治性，科学驱动的理解和治疗方法对于 CDKL5 至关重要紊乱。拟议的研究旨在 1) 确定预测因子并定义 CDKL5 的流行病学疾病，2) 建立 CDKL5 疾病的基因型-表型相关性，以及 3) 评估 CDKL5 相关的癫痫痉挛接受标准治疗。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early diagnosis and experimental treatment with fenfluramine via the Investigational New Drug mechanism in a boy with Dravet syndrome and recurrent status epilepticus.

通过研究新药机制对患有 Dravet 综合征和复发性癫痫持续状态的男孩进行早期诊断和实验性治疗。

DOI：
10.1684/epd.2021.1345
发表时间：
2021-12-01
期刊：
Epileptic disorders : international epilepsy journal with videotape
影响因子：
0
作者：
Trowbridge S;Poduri A;Olson H
通讯作者：
Olson H

Towards understanding genetic risk in febrile seizures: innate immunity and neuronal excitability.

了解热性惊厥的遗传风险：先天免疫和神经元兴奋性。

DOI：
10.1093/brain/awac036
发表时间：
2022
期刊：
Brain : a journal of neurology
影响因子：
0
作者：
Olson,HeatherE;Poduri,Annapurna
通讯作者：
Poduri,Annapurna

CDKL5 deficiency disorder: clinical features, diagnosis, and management.

DOI：
10.1016/s1474-4422(22)00035-7
发表时间：
2022-06
期刊：
LANCET NEUROLOGY
影响因子：
48
作者：
Leonard, Helen;Downs, Jenny;Benke, Tim A.;Swanson, Lindsay;Olson, Heather;Demarest, Scott
通讯作者：
Demarest, Scott

CDKL5 deficiency disorder and other infantile-onset genetic epilepsies.

CDKL5 缺乏症和其他婴儿期发病的遗传性癫痫。

DOI：
10.1111/dmcn.15747
发表时间：
2024
期刊：
Developmental medicine and child neurology
影响因子：
3.8
作者：
Daniels,Carolyn;Greene,Caitlin;Smith,Lacey;Pestana-Knight,Elia;Demarest,Scott;Zhang,Bo;Benke,TimothyA;Poduri,Annapurna;Olson,HeatherE;CDKL5StudyGroup
通讯作者：
CDKL5StudyGroup

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

CDKL5 缺乏症中的癫痫痉挛：治疗延迟且对一线治疗反应不佳。

DOI：
10.1111/epi.17630
发表时间：
2023
期刊：
Epilepsia
影响因子：
5.6
作者：
Olson,HeatherE;Demarest,Scott;Pestana-Knight,Elia;Moosa,AhsanN;Zhang,Xiaoming;Pérez-Pérez,JoséR;Weisenberg,Judy;O'ConnorPrange,Erin;Marsh,EricD;Rajaraman,RajsekarR;Suter,Bernhard;Katyayan,Akshat;Haviland,Isabel;Daniels,Car
通讯作者：
Daniels,Car