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.

Public Health Relevance

Health effects of myotonic dystrophy, the most common form of muscular dystrophy in adults, are profound, in part because this complex disorder significantly affects the brain. Through detailed studies of brain structure (using novel MRI analyses) and function (physiological and psychological), the proposed investigations will help define the causes and treatments of this devastating dominantly inherited disorder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Nakamori, Masayuki; Hamanaka, Kohei; Thomas, James D et al. (2017) Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep 21:1240-1252
Cleary, John Douglas; Ranum, Laura Pw (2017) New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev 44:125-134
Thomas, James D; Sznajder, ?ukasz J; Bardhi, Olgert et al. (2017) Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy. Genes Dev 31:1122-1133
Moloney, Christina; Rayaprolu, Sruti; Howard, John et al. (2016) Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype. Acta Neuropathol Commun 4:122
Taliaferro, J Matthew; Vidaki, Marina; Oliveira, Ruan et al. (2016) Distal Alternative Last Exons Localize mRNAs to Neural Projections. Mol Cell 61:821-33
Freyermuth, Fernande; Rau, Frédérique; Kokunai, Yosuke et al. (2016) Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun 7:11067
Scotti, Marina M; Swanson, Maurice S (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19-32
Hewitt, Angela L; Popa, Laurentiu S; Ebner, Timothy J (2015) Changes in Purkinje cell simple spike encoding of reach kinematics during adaption to a mechanical perturbation. J Neurosci 35:1106-24
Goodwin, Marianne; Mohan, Apoorva; Batra, Ranjan et al. (2015) MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain. Cell Rep 12:1159-68
Coram, Ryan J; Stillwagon, Samantha J; Guggilam, Anuradha et al. (2015) Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev Biol 15:36

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