Structural and Functional CNS Changes in Myotonic Dystrophy Types 1 and 2

描述(申请人提供)：强直性肌营养不良症(DM)是最常见的肌营养不良症之一，是一种由19号染色体(DM1)或3号染色体(DM2)突变引起的多系统疾病。DM1突变的病理生理效应一直存在争议，因为它是基因3‘端未翻译的CTG扩展，从而导致这种严重的显性遗传病，而不影响基因的编码部分。DM2是由类似的未翻译的CCTG扩增引起的这一发现，以及关于DM1发病机制的其他发现，帮助定义了一种新的疾病机制，在这种机制中，两种疾病都是由有毒的RNA机制引起的：带有CUG或CCUG扩张的转录本收集在细胞核中，并影响细胞功能，至少部分是通过改变下游基因的剪接。我们对DM1和DM2的比较表明，这两种疾病的共同特征可能是这些RNA效应造成的。糖尿病的发病率很大程度上是由CMS缺陷引起的，最显著的是只在DM1中出现的精神发育迟缓。由于DM1和DM2的CMS效应不同，它们是否由改变的RNA处理引起的争议是有争议的。我们的初步定量研究现在显示，DM1和DM2的MRI和功能CNS发生了类似的变化，这意味着有毒的RNA导致了这些影响：1)额叶体积的损失；2)扩散张量成像测量的额叶白质异常；3)执行、功能改变的趋势，与额叶结构变化一致。由于DM2纯粹是迟发的，两种形式的DM常见的中枢神经系统效应很可能是由神经退行性变引起的，除了定义神经发育DM1的影响外，我们还将通过对四组严格定义的成年人进行横断面和纵向研究来表征神经退行性变：成年型DM1、成年型DM2、先天性DM1和正常对照组。这些研究将确定可能由RNA毒性引起的DM1和DM2的共同中枢神经系统特征，以及需要阐明其病理生理机制的差异。我们还将确定受试者的基因特征，并保持细胞培养，这将有助于我们正在进行的尸检材料的收集，以帮助未来的分子和细胞研究。我们庞大的DM受试者群体，以及我们独特的成像和神经心理学能力，现在将帮助我们了解DM的毁灭性的中枢神经系统特征。

DESCRIPTION (provided by applicant): Myotonic Dystrophy (DM), one of the most common forms of muscular dystrophy, is a multisystemic disorder caused by mutations on either chromosome 19 (DM1) or chromosome 3 (DM2). The pathophysiological effects of the DM1 mutation have been controversial because it is an untranslated CTG expansion in the 3' region of a gene, and thus causes this severe dominantly inherited disease without affecting the coding portion of a gene. The discovery that DM2 is caused by a similarly untranslated CCTG expansion, along with other discoveries about DM1 pathogenesis, have helped define a new disease mechanism in which both diseases are caused by a toxic RNA mechanism: transcripts with CUG or CCUG expansions collect in nuclei and affect cell function, at least in part by altering splicing of downstream genes. Our comparisons of DM1 and DM2 have shown that the features common to both diseases likely result from these RNA effects. Much of DM morbidity results from CMS deficits, most dramatically the mental retardation that is only seen in DM1. Because CMS effects differ in DM1 and DM2, whether they are caused by altered RNA processing is controversial. Our preliminary quantitative studies now show comparable MRI and functional CNS changes in DM1 and DM2, implying a toxic RNA cause these effects: 1) loss of frontal lobe volume; 2) frontal white matter abnormalities measured by diffusion tensor imaging; 3) trends toward altered executive, function consistent with the frontal lobe structural changes. Because DM2 is purely late-onset, CNS effects that are common to both forms of DM are likely caused by neurodegeneration, which we will characterize, in addition to defining neurodevelopmental DM1 effects, by cross-sectional and longitudinal studies of four strictly defined groups of adults: adult-onset DM1, adult-onset DM2, congenital DM1, and normal controls. These studies will identify CNS features common to DM1 and DM2 that likely result from RNA toxicity, as well as differences for which pathophysiological mechanisms will need to be clarified. We will also genetically characterize subjects, and maintain cell cultures, which with our ongoing collection of autopsy material will help in future molecular and cellular studies. Our large population of DM subjects, and our unique imaging and neuropsychological capabilities, will now help us understand the devastating CNS features of DM.