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：
8739679
负责人：
JOHN W DAY
金额：
$ 24.86万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8739679
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 Elements Evoked Potentials Family Functional disorder Funding Future Genetic Health Human Impaired cognition Inborn Genetic Diseases Inherited Investigation Laboratories Lead Magnetic Resonance Imaging Measurement Measures 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 cognitive function common treatment design executive function family genetics hypocretin improved infancy insight mouse model neuropsychological novel optimism pre-clinical processing speed psychologic response sleep abnormalities 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.

1 型强直性肌营养不良的中枢神经系统结构和功能异常强直性肌营养不良 (DM) 是最常见的肌营养不良形式，可引起无与伦比的巨大多系统效应。 DM 复杂的临床表现是由广泛的潜在分子变化引起的，包括至少部分由 RNA 结合蛋白 MBNL 的隔离引起的基因转录本家族的错误处理。复杂的 DM 表型遵循多阶段的时间过程，其中特定特征出现在从婴儿期到成年的不同年龄，每个 DM 患者都具有重叠的发育、退行性和生理缺陷。临床对糖尿病骨骼肌的关注虽然很重要，但可能会掩盖该疾病对中枢神经系统的破坏性影响，包括：发育性认知障碍、执行功能进行性丧失、人格和行为改变、自闭症谱系中的社交互动和中枢性嗜睡。为了阐明病理生理学并促进中枢神经系统效应的治疗，拟议的研究将定量描述一个临床上重要但定义不明确的特征，即中枢性嗜睡，这是一种可能对药物或基因治疗产生显着反应的生理异常。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，包括白质完整性改变（使用新的 MRI 测量）、执行功能丧失和脑脊液异常测量。虽然人们对用反义寡核苷酸治疗糖尿病骨骼肌越来越乐观，但拟议的研究现在将有助于阐明分子病理生理学，同时还定义研究中枢神经系统对治疗的反应的方法，并建立将小鼠模型与临床疾病进行比较的方法，从而为未来提供详细的见解探讨这种常见、复杂和毁灭性疾病的病因和治疗方法。