CLINICAL AND GENETIC CHARACTERIZATION OF MYOTONIC DYSTROPHY

强直性肌营养不良的临床和遗传特征

基本信息

批准号：
9105457
负责人：
JOHN W DAY
金额：
$ 24.54万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105457
关键词：
Address Adult Affect Age Animal Model Antisense Oligonucleotides Autistic Disorder Behavioral Biological Markers Brain Clinical Clinical Research Clinical Trials Cognition Cognitive Complement Complex Cross-Over Studies Development Diffuse Disease Electroencephalography Electrophysiology (science)Elements Evoked Potentials Family Functional disorder Funding Future Genetic Genetic study Health Human Impaired cognition Inborn Genetic Diseases Inherited Investigation Laboratories Lead Magnetic Resonance Imaging Measurement Measures Medical Genetics Methods Modafinil Modeling Molecular Morbidity - disease rate Mus Muscular Dystrophies Mutant Strains Mice Myotonic Dystrophy Names Neonatal Outcome Measure Pathogenesis Pathology Patients Pattern Personality Pharmaceutical Preparations Phenotype Physiological Physiology Polysomnography Proteins Questionnaires REM Sleep RNA RNA Splicing RNA-Binding Proteins Role Sampling Short-Term Memory Skeletal Muscle Sleep Sleep Architecture Sleep Disorders Social Interaction Structure Testing Time Transcript Translations actigraphy atomoxetine biomarker identification clinical investigation cognitive function common treatment design executive function family genetics hypocretin improved infancy insight mouse model neuropsychological novel optimism pre-clinical processing speed psychologic sleep abnormalities symptom treatment treatment response white matter white matter change young adult

项目摘要

Structural and Functional CNS Abnormalities in Myotonic Dystrophy type 1 Myotonic dystrophy (DM), the most common form of muscular dystrophy, causes dramatic unparalleled multisystemic effects. The complicated clinical presentation of DM results from broad underlying molecular changes, including misprocessing of a family of genetic transcripts caused, at least in part, by sequestration of the RNA binding protein, MBNL. The complex DM phenotype follows a multiphasic time course, in which specific features appear at various ages from infancy through adulthood, each DM patient having overlapping developmental, degenerative and physiological deficits. Clinical focus on skeletal muscle in DM, although important, can obscure the devastating CNS effects of the disorder, including: developmental cognitive impairment, progressive loss of executive function, personality and behavioral changes, social interactions in the autism spectrum, and central hypersomnia. To clarify pathophysiology, and facilitate treatment of the CNS effects, the proposed studies will quantitatively characterize a clinically important but poorly defined feature, central hypersomnia, a physiological abnormality that may measurably respond to pharmacologic or genetic treatment. The sleep abnormality will be studied in the context of other defined CNS features including altered white matter integrity (using novel MRI measures), loss of executive function and measurement of CSF abnormalities. While optimism has grown for treating skeletal muscle in DM with antisense oligonucleotides, the proposed studies will now help clarify molecular pathophysiology while also defining methods for studying CNS response to treatment, and establishing methods to compare mouse models with the clinical disorder, allowing future detailed insights into the cause and treatment of this common, complex and devastating disease.

肌发育症1型的结构和功能性中枢神经系统异常肌营养不良症（DM）是肌肉营养不良的最常见形式，会引起戏剧性的无与伦比的多系统作用。 DM的复杂临床表现引起的是潜在的分子变化，包括对RNA结合蛋白MBNL的隔离引起的遗传转录家族的错误处理。复杂的DM表型遵循多相时间的过程，其中特定特征从婴儿期到成年期都出现在各个年龄段，每个DM患者都有重叠的发育，退化性和生理缺陷。对DM中骨骼肌的临床关注虽然很重要，但仍可以掩盖该疾病的毁灭性中枢神经系统作用，包括：发育认知障碍，执行功能的逐步逐渐丧失，人格和行为变化，自闭症谱系中的社交相互作用和中央高血压。为了澄清病理生理学并促进中枢神经系统作用的治疗，拟议的研究将定量地表征临床上重要但定义较差的特征，中枢性性高症，这是一种生理异常，可以对药理或遗传治疗有所反应。睡眠异常将在其他定义的中枢神经系统特征的背景下进行研究，包括改变白质完整性（使用新型MRI测量），执行功能的丧失和CSF异常的测量。尽管对使用反义寡核苷酸的DM治疗DM的骨骼肌的乐观情绪已越来越兴奋，但拟议的研究现在将有助于阐明分子病理生理学，同时还定义了研究中枢神经系统对治疗的反应的方法，并建立了将小鼠模型与临床障碍进行比较的方法，从而使这种常见的疾病和discession疾病的详细介绍和治疗。