CLINICAL AND GENETIC CHARACTERIZATION OF MYOTONIC DYSTROPHY

强直性肌营养不良1型患者的中枢神经系统结构和功能异常 强直性肌营养不良症(DM)是最常见的肌营养不良症，可引起前所未有的多系统影响。糖尿病复杂的临床表现是广泛的潜在分子变化的结果，包括一系列基因转录本的错误处理，至少部分是由于RNA结合蛋白MBNL的隔离引起的。复杂的DM表型遵循一个多阶段的时间过程，从婴儿期到成年期在不同的年龄出现特定的特征，每个DM患者都有重叠的发育、退行性和生理缺陷。临床上对糖尿病患者骨骼肌的关注虽然重要，但可以掩盖这种疾病对中枢神经系统的破坏性影响，包括：发育认知障碍、执行功能进行性丧失、个性和行为变化、自闭症谱系中的社会互动以及中枢性睡眠过度。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-中枢性睡眠过度，这是一种生理异常，可能对药物或基因治疗有可测量的反应。睡眠异常将在其他明确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测量方法)、执行功能丧失和脑脊液异常的测量。虽然人们对用反义寡核苷酸治疗糖尿病的骨骼肌持乐观态度，但拟议的研究现在将有助于澄清分子病理生理学，同时还将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，使未来能够详细了解这种常见、复杂和毁灭性疾病的病因和治疗。

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.