Structural and Functional CNS Changes in Children with Myotonic Dystrophy Type 1 Myotonic Dystrophy (DM), the most prevalent form of muscular dystrophy, is a multisystemic disorder caused by mutations on chromosome 19 (DM1) or chromosome 3 (DM2). The pathophysiological effects of the DM1 mutation are controversial because it is an untranslated CTG expansion, and thus causes this progressive and ultimately fatal disease without altering the coding portion of any 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 RNA containing CUG or CCUG expansions affects cell function, at least partly by altering splicing of many genes. Our comparisons of DM1 and DM2 show that features common to both diseases result from these RNA effects, though controversy remains as to the molecular pathophysiology of features that differ in the two forms of DM. Much of DM morbidity results from CNS deficits. Because some CNS effects differ in DM1 and DM2, the role of the toxic RNA mechanism in CNS pathophysiology is controversial. We have defined CNS MRI and neuropsychological changes in DM children and adults, including: 1) loss of frontal lobe volume;2) frontal white matter disorganization measured by diffusion tensor imaging;3) altered executive function. The CNS abnormalities common to DM1 and DM2 almost certainly result from the toxic-RNA mechanism. We now propose to investigate children with early-onset DM1 to better define the structural and functional CNS abnormalities.
Our specific aims are to: 1) determine whether early-onset DM1 causes structural CNS deficits in children that are similar to adult-onset DM1 and DM2;2) determine whether children with DM1 have neuropsychological deficits that correspond to the structural abnormalities;3) to determine the molecular features of early-onset DM1 by establishing whether repeat length or methylation status alter the likelihood of CNS involvement;4) to develop a clinically useful measure of CNS involvement for future DM natural history and therapeutic trials. The proposed studies will improve our understanding of CNS involvement in patients with DM, and will inform the transgenic animal and molecular studies being performed in Projects 1 and 2 and in the Core of this Program. Together with Projects 1 and 2, this overall Program will elucidate clinical, cellular and molecular elements of CNS disease in DM, and help identify and evaluate therapeutic targets.
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