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.
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