CLINICAL AND GENETIC CHARACTERIZATION OF MYOTONIC DYSTROPHY

强直性肌营养不良1型的结构和功能中枢神经系统异常 强直性肌营养不良症（DM）是肌营养不良症最常见的形式，引起戏剧性的无与伦比的多系统影响。DM的复杂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的螯合引起的遗传转录物家族的错误处理。复杂的DM表型遵循多相时程，其中特定特征出现在从婴儿期到成年期的不同年龄，每个DM患者具有重叠的发育、退行性和生理缺陷。临床上对DM骨骼肌的关注虽然重要，但可能会掩盖该疾病的破坏性CNS影响，包括：发育性认知障碍、执行功能的进行性丧失、人格和行为变化、自闭症谱系中的社会互动和中枢性嗜睡。为了阐明病理生理学，并促进CNS效应的治疗，拟定的研究将定量描述一种临床重要但定义不明确的特征，中枢性嗜睡，一种可能对药理学或遗传治疗有可测量反应的生理异常。将在其他定义的CNS特征的背景下研究睡眠异常，包括改变的白色物质完整性（使用新的MRI测量）、执行功能丧失和CSF异常测量。虽然用反义寡核苷酸治疗DM骨骼肌的乐观情绪已经增长，但拟议的研究现在将有助于澄清分子病理生理学，同时还定义了研究CNS对治疗反应的方法，并建立了将小鼠模型与临床疾病进行比较的方法，允许未来详细了解这种常见，复杂和毁灭性疾病的原因和治疗。

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.