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Trends in Cardiovascular Medicine May 2020Patients with myotonic dystrophy, the most common neuromuscular dystrophy in adults, have a high prevalence of arrhythmic complications with increased cardiovascular... (Review)
Review
Patients with myotonic dystrophy, the most common neuromuscular dystrophy in adults, have a high prevalence of arrhythmic complications with increased cardiovascular mortality and high risk for sudden death. Sudden death prevention is central and relies on annual follow-up and prophylactic permanent pacing in patients with conduction defects on electrocardiogram and/or infrahisian blocks on electrophysiological study. Implantable cardiac defibrillator therapy may be indicated in patients with ventricular tachyarrhythmia.
Topics: Animals; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Death, Sudden, Cardiac; Defibrillators, Implantable; Electric Countershock; Genetic Predisposition to Disease; Humans; Myotonic Dystrophy; Pacemaker, Artificial; Prevalence; Risk Factors; Treatment Outcome
PubMed: 31213350
DOI: 10.1016/j.tcm.2019.06.001 -
JACC. Clinical Electrophysiology Dec 2021
Topics: Cardiac Conduction System Disease; Humans; Myotonic Dystrophy
PubMed: 34949430
DOI: 10.1016/j.jacep.2021.10.005 -
Clinical and Molecular Insights into Gastrointestinal Dysfunction in Myotonic Dystrophy Types 1 & 2.International Journal of Molecular... Nov 2022Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the... (Review)
Review
Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the symptoms and pathological mechanisms affecting striated muscle and brain, DM patient surveys have identified a high prevalence for gastrointestinal (GI) symptoms amongst affected individuals. Clinical studies have identified chronic and progressive dysfunction of the esophagus, stomach, liver and gallbladder, small and large intestine, and rectum and anal sphincters. Despite the high incidence of GI dysmotility in DM, little is known regarding the pathological mechanisms leading to GI dysfunction. In this review, we summarize results from clinical and molecular analyses of GI dysfunction in both genetic forms of DM, DM type 1 (DM1) and DM type 2 (DM2). Based on current knowledge of DM primary pathological mechanisms in other affected tissues and GI tissue studies, we suggest that misregulation of alternative splicing in smooth muscle resulting from the dysregulation of RNA binding proteins muscleblind-like and CUGBP-elav-like is likely to contribute to GI dysfunction in DM. We propose that a combinatorial approach using clinical and molecular analysis of DM GI tissues and model organisms that recapitulate DM GI manifestations will provide important insight into defects impacting DM GI motility.
Topics: Humans; Myotonic Dystrophy; Alternative Splicing; Muscle, Skeletal; RNA-Binding Proteins
PubMed: 36499107
DOI: 10.3390/ijms232314779 -
International Journal of Molecular... May 2020Myopathies represent a wide spectrum of heterogeneous diseases mainly characterized by the abnormal structure or functioning of skeletal muscle. The current paper... (Review)
Review
Myopathies represent a wide spectrum of heterogeneous diseases mainly characterized by the abnormal structure or functioning of skeletal muscle. The current paper provides a comprehensive overview of cognitive deficits observed in various myopathies by consulting the main libraries (Pubmed, Scopus and Google Scholar). This review focuses on the causal classification of myopathies and concomitant cognitive deficits. In most studies, cognitive deficits have been found after clinical observations while lesions were also present in brain imaging. Most studies refer to hereditary myopathies, mainly Duchenne muscular dystrophy (DMD), and myotonic dystrophies (MDs); therefore, most of the overview will focus on these subtypes of myopathies. Most recent bibliographical sources have been preferred.
Topics: Brain; Cognitive Dysfunction; Humans; Muscular Dystrophy, Duchenne; Myotonic Dystrophy
PubMed: 32471196
DOI: 10.3390/ijms21113795 -
Comprehensive Physiology Mar 2018Myotonic dystrophy (DM) is a multisystemic disorder caused by microsatellite expansion mutations in two unrelated genes leading to similar, yet distinct, diseases. DM... (Review)
Review
Myotonic dystrophy (DM) is a multisystemic disorder caused by microsatellite expansion mutations in two unrelated genes leading to similar, yet distinct, diseases. DM disease presentation is highly variable and distinguished by differences in age-of-onset and symptom severity. In the most severe form, DM presents with congenital onset and profound developmental defects. At the molecular level, DM pathogenesis is characterized by a toxic RNA gain-of-function mechanism that involves the transcription of noncoding microsatellite expansions. These mutant RNAs disrupt key cellular pathways, including RNA processing, localization, and translation. In DM, these toxic RNA effects are predominantly mediated through the modulation of the muscleblind-like and CUGBP and ETR-3-like factor families of RNA binding proteins (RBPs). Dysfunction of these RBPs results in widespread RNA processing defects culminating in the expression of developmentally inappropriate protein isoforms in adult tissues. The tissue that is the focus of this review, skeletal muscle, is particularly sensitive to mutant RNA-responsive perturbations, as patients display a variety of developmental, structural, and functional defects in muscle. Here, we provide a comprehensive overview of DM1 and DM2 clinical presentation and pathology as well as the underlying cellular and molecular defects associated with DM disease onset and progression. Additionally, fundamental aspects of skeletal muscle development altered in DM are highlighted together with ongoing and potential therapeutic avenues to treat this muscular dystrophy. © 2018 American Physiological Society. Compr Physiol 8:509-553, 2018.
Topics: Animals; Gene Expression Regulation, Developmental; Humans; Muscle Development; Muscle, Skeletal; Mutation; Myotonic Dystrophy; Pedigree; RNA-Binding Proteins
PubMed: 29687899
DOI: 10.1002/cphy.c170002 -
Drug Discovery Today Dec 2018Myotonic dystrophy 1 (DM1) is a multisystemic neuromuscular disease caused by a dominantly inherited 'CTG' repeat expansion in the gene encoding DM Protein Kinase... (Review)
Review
Myotonic dystrophy 1 (DM1) is a multisystemic neuromuscular disease caused by a dominantly inherited 'CTG' repeat expansion in the gene encoding DM Protein Kinase (DMPK). The repeats are transcribed into mRNA, which forms hairpins and binds with high affinity to the Muscleblind-like (MBNL) family of proteins, sequestering them from their normal function. The loss of function of MBNL proteins causes numerous downstream effects, primarily the appearance of nuclear foci, mis-splicing, and ultimately myotonia and other clinical symptoms. Antisense and other RNA-mediated technologies have been applied to target toxic-repeat mRNA transcripts to restore MBNL protein function in DM1 models, such as cells and mice, and in humans. This technique has had promising results in DM1 therapeutics by alleviating pathogenic phenotypes.
Topics: Animals; Humans; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA; RNA, Messenger
PubMed: 30086404
DOI: 10.1016/j.drudis.2018.08.004 -
International Journal of Cardiology Apr 2015Myotonic dystrophy (MD) is a multisystem, autosomal dominant disorder best known for its skeletal muscle manifestations. Cardiac manifestations arise as a result of... (Review)
Review
UNLABELLED
Myotonic dystrophy (MD) is a multisystem, autosomal dominant disorder best known for its skeletal muscle manifestations. Cardiac manifestations arise as a result of myocardial fatty infiltration, degeneration and fibrosis and present most commonly as arrhythmias or conduction disturbances. Guidelines regarding the optimal cardiac management of patients with MD are lacking. The present article provides a summary of the pathophysiology of cardiac problems in patients with MD and provides a practical approach to contemporary cardiac monitoring and management of these patients with a focus on the prevention of complications related to conduction disturbances and arrhythmias.
METHODS
A literature search was performed using PubMed and Medline. The keywords used in the search included "myotonic dystrophy", "cardiac manifestations", "heart", "arrhythmia", "pacemaker" and "defibrillator", all terms were used in combination. In addition, "myotonic dystrophy" was searched in conjunction with "electrophysiology", "electrocardiogram", "echocardiograph", "signal averaged electrocardiograph", "magnetic resonance imaging" and "exercise stress testing". The titles of all the articles revealed by the search were screened for relevance. The abstracts of relevant titles were read and those articles which concerned the cardiac manifestations of myotonic dystrophy or the investigation and management of cardiac manifestations underwent a full manuscript review.
Topics: Animals; Disease Management; Echocardiography; Electrocardiography; Heart Diseases; Humans; Myotonic Dystrophy
PubMed: 25769007
DOI: 10.1016/j.ijcard.2015.03.069 -
Seminars in Neurology Dec 2022The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography...
The diagnosis of neuromuscular disorders requires a thorough history including family history and examination, with the next steps broadened now beyond electromyography and neuropathology to include genetic testing. The challenge in diagnosis can often be putting all the information together. With advances in genetic testing, some diagnoses that adult patients may have received as children deserve a second look and may result in diagnoses better defined or alternative diagnoses made. Clearly defining or redefining a diagnosis can result in understanding of potential other systems involved, prognosis, or potential treatments. This article presents several cases and approach to diagnosis as well as potential treatment and prognostic concerns, including seipinopathy, congenital myasthenic syndrome, central core myopathy, and myotonic dystrophy type 2.
Topics: Child; Adult; Humans; Neuromuscular Diseases; Electromyography; Genetic Testing; Myotonic Dystrophy
PubMed: 36417990
DOI: 10.1055/a-1985-0230 -
Muscle & Nerve Sep 2020Myotonic dystrophies (DM), the most common muscular dystrophies, are known to have significant sleep disturbances. We analyzed the literature on sleep and excessive... (Review)
Review
Myotonic dystrophies (DM), the most common muscular dystrophies, are known to have significant sleep disturbances. We analyzed the literature on sleep and excessive daytime sleepiness (EDS) in DM over the past 30 years. In this review we provide a brief overview of sleep, sleep disorders, and methods of assessment. We also analyze data regarding major sleep disorders in DM patients, including: sleep-disordered breathing (SDB), with both central and obstructive sleep apneas (CSA,OSA); EDS; sleep-related movement disorders; and poor sleep quality. We review the possible pathogenesis of these disorders and outline management strategies. We also consider possible future avenues for research. The findings highlight the complex set of sleep-related problems, including the primary abnormality of sleep control in myotonic dystrophies. In individual patients the roles of poor sleep hygiene, SDB, primary hypersomnia, and excess fatigue require careful assessment for appropriate management.
Topics: Fatigue; Humans; Myotonic Dystrophy; Sleep Wake Disorders
PubMed: 32212331
DOI: 10.1002/mus.26866 -
Journal of Translational Medicine Dec 2022Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3' untranslated...
BACKGROUND
Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3' untranslated region of the DMPK gene. The CUG repeats transcribed from the expanded CTG repeats sequestrate a splicing factor, MBNL1, causing the clinical symptoms in DM1. Nowadays, only symptomatic treatments are available for DM1, and no rational therapy is available. Recently, upregulation of MBNL1 expression has been found to be one of the promising therapies for DM1.
METHODS
All experiments were conducted in the C2C12 myoblasts and HSA mice, a DM1 mouse model. Real-time PCR and western blot were used to detect the mRNA and protein level, respectively. The rotarod exercise, grip strength and hanging time were used to evaluate the muscle strength of mice.
RESULTS
In this study, we demonstrated that calcitriol, an active form of vitamin D3, increased MBNL1 in C2C12 mouse myoblasts as well as in HSA mice model for DM1. In HSA mice model, calcitriol improved muscle strength, and corrected aberrant splicing in skeletal muscle. Besides, calcitriol reduced the number of central nuclei, and improved muscle histopathology in HSA mice. In addition, we identified that calcitriol upregulated MBNL1 expression via activating the promoter of Mbnl1 in C2C12 myogenic cells.
CONCLUSION
Our study suggests that calcitriol is a potential pharmacological strategy for DM1 that enhances MBNL1 expression.
Topics: Mice; Animals; Myotonic Dystrophy; Calcitriol; RNA-Binding Proteins; Myoblasts; Disease Models, Animal; Muscle, Skeletal; Alternative Splicing; DNA-Binding Proteins
PubMed: 36510245
DOI: 10.1186/s12967-022-03806-9