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

描述（由申请人提供）：强直性肌营养不良症（DM）是肌营养不良症的最常见形式之一，是由19号染色体（DM 1）或3号染色体（DM 2）上的突变引起的多系统性疾病。DM 1突变的病理生理学效应一直存在争议，因为它是基因3'区的非翻译CTG扩增，因此导致这种严重的显性遗传疾病，而不影响基因的编码部分。发现DM 2是由类似的非翻译的CCTG扩增引起的，沿着关于DM 1发病机制的其他发现，帮助定义了一种新的疾病机制，其中两种疾病都是由毒性RNA机制引起的：具有CUG或CCUG扩增的转录物聚集在细胞核中并影响细胞功能，至少部分通过改变下游基因的剪接。我们对DM 1和DM 2的比较表明，这两种疾病的共同特征可能是由这些RNA效应引起的。大部分DM发病率由CMS缺陷引起，最显著的是仅见于DM 1的智力迟钝。由于CMS效应在DM 1和DM 2中不同，它们是否由改变的RNA加工引起是有争议的。我们的初步定量研究显示，DM 1和DM 2的MRI和功能性CNS变化相当，这意味着毒性RNA导致这些影响：1）额叶体积损失; 2）通过扩散张量成像测量的额叶白色物质异常; 3）执行功能改变的趋势与额叶结构变化一致。由于DM 2是纯粹的迟发性，两种形式的DM共同的CNS效应可能是由神经变性引起的，除了定义神经发育DM 1效应外，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变性：成人发病DM 1，成人发病DM 2，先天性DM 1和正常对照。这些研究将确定可能由RNA毒性引起的DM 1和DM 2共同的CNS特征，以及需要澄清的病理生理机制的差异。我们还将对受试者进行基因鉴定，并保持细胞培养，这与我们正在进行的尸检材料收集将有助于未来的分子和细胞研究。我们庞大的糖尿病受试者群体，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糖尿病的破坏性CNS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.