CLINICAL AND GENETIC CHARACTERIZATION OF MYOTONIC DYSTROPHY

强直性肌营养不良的临床和遗传特征

• 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
• 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

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进程，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，从而使未来能够详细了解这种常见、复杂和毁灭性疾病的原因和治疗。