Myotonic dystrophy types 1 and 2

Ashizawa, Tetsuo; Sarkar, Partha S.

doi:10.1016/b978-0-08-045031-5.00015-3

Cited by 61 publications

(48 citation statements)

References 320 publications

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“…DM1 can be progressive or congenital, manifesting in children and adults with muscle weakness and myotonia and in neonates with generalized hypotonia. 75,81 Diagnosis is confirmed by genetic testing, with affected individuals having >35 trinucleotide repeats. In general, longer repeat expansion correlates with higher penetrance, earlier onset, and increased severity of disease.…”

Section: Myotonic Dystrophymentioning

confidence: 99%

“…[82][83][84] There is a tendency for successive generations to show symptoms at an earlier age or with more severe manifestations (ie, anticipation). 75,85 Similar to DM1, DM2 is a multisystem disease characterized primarily by myotonia and muscle wasting. 80,86 DM2 is caused by expansion of a CCTG repeat in intron 1 of CNBP (encoding CCHC-type zinc finger, nucleic acid binding protein).…”

Section: Myotonic Dystrophymentioning

confidence: 99%

“…There are 2 recognized forms of DM: myotonic dystrophy type 1 (DM1), also known as Steinert disease, and myotonic dystrophy type 2 (DM2), also known as proximal myotonic myopathy (PROMM) or Ricker disease. 75 Both DM types are inherited in an autosomal dominant manner and share a common core of clinical manifestations. It is probable that pathology is associated with intracellular disruption of the RNA transcript-processing machinery in affected cells.…”

Section: Myotonic Dystrophymentioning

confidence: 99%

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Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Feingold¹,

Mahle²,

Auerbach³

et al. 2017

Circulation

211

195

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For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes. N euromuscular diseases (NMDs) encompass a broad spectrum of diagnoses with overlapping but distinct phenotypes. Common to many NMDs is cardiac involvement. Although the past 3 decades have seen marked advances in our understanding of many NMDs, significant gaps in knowledge remain on how best to approach cardiac care in these patients. For example, survival in Duchenne muscular dystrophy (DMD) has been extended through the use of glucocorticoid use and respiratory support, yet cardiac complications remain a significant cause of morbidity and mortality.1-3 To achieve further gains in care, we will need to improve our understanding of the pathophysiologies driving cardiac involvement in NMDs and advance treatments aimed at preventing the progression of heart failure (HF) and sudden death in NMDs. The recently published findings of an expert working group on cardiac involvement in DMD, which outlined key gaps in knowledge and made specific recommendations aimed at improving diagnosis and management, are a step toward this goal. 4 In this statement, we include a comprehensive overview of the major categories of NMDs with cardiac involvement. For each, a brief background of the gene defect(s), common clinical manifestations (particularly cardiac findings), and current therapies is summarized. Gaps in knowledge are highlighted, and where possible, clinical treatment suggestions are made by the expert writing group appointed by the American Heart Association to review the available literature. Selection of the writing group was performed in accordance with the American Heart Association's conflict-of-interest management policy. Participants volunteered to write sections relevant to their expertise and experience. CLINICAL STATEMENTS AND GUIDELINESconducted a general search of the literature, restricted to human subjects research published between 1980 and 2016. Drafts of each section were written and sent to the chair of the writing group for incorporation into a single document, which was then edited. The edited document was discussed electron...

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Section: Myotonic Dystrophymentioning

confidence: 99%

Section: Myotonic Dystrophymentioning

confidence: 99%

Section: Myotonic Dystrophymentioning

confidence: 99%

See 1 more Smart Citation

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Feingold¹,

Mahle²,

Auerbach³

et al. 2017

Circulation

211

195

View full text Add to dashboard Cite

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“…In these foci, CUG exp RNA sequesters splicing factors, including MBNL 1 and 2, which results in splicing dysregulation of many target gene transcripts. Dysregulated splicing has been found to be responsible for specific phenotypes of DM1, including myotonia and insulin insufficiency (Ashizawa and Sarkar, 2011; de Leon and Cisneros, 2008; Lee and Cooper, 2009; Llamusi and Artero, 2008; Ranum and Cooper, 2006; Schara and Schoser, 2006). Thus, nuclear RNA foci containing expanded CUG repeats are the molecular hallmark of the RNA gain-of-function pathomechanism of DM1.…”

Section: Introductionmentioning

confidence: 99%

Dynamic changes of nuclear RNA foci in proliferating DM1 cells

Xia

Ashizawa

2015

Histochem Cell Biol

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Introduction Nuclear RNA foci are molecular hallmarks of myotonic dystrophy type 1 (DM1). However, no designated study has investigated their formation and changes in proliferating cells. Proliferating cells, as stem cells, consist of an important cellular pool in the human body. The revelation of foci changes in these cells might shed light on the effects of the mutation on these specific cells and tissues. In this study, we used human DM1 iPS-cell derived neural stem cells (NSCs) as cellular models to investigate the formation and dynamic changes of RNA foci in proliferating cells. Materials and Methods Human DM1 NSCs derived from human DM1 iPS cells were cultured under proliferation conditions and non-proliferation conditions following Mitomycin C treatment. The dynamic changes of foci during the cell cycle were investigated by fluorescence in situ hybridization (FISH). Results We found RNA foci formed and dissociated during the cell cycle. Nuclear RNA foci were most prominent in number and size just prior to entering mitosis (early prophase). During mitosis, most foci disappeared. After entering interphase, RNA foci accumulated again in the nuclei. After stopping cell dividing by treatment of Mitomycin C, the number of nuclear RNA foci increased significantly. Conclusion DM1 NSC nuclear RNA foci undergo dynamic changes during cell cycle and mitosis is a mechanism to decrease foci load in the nuclei, which may explain why dividing cells are less affected by the mutation. The dynamic changes need to be considered when using foci as a marker to monitor the effects of therapeutic drugs.

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“…Myotonic dystrophy type I is a multisystem disorder with patients showing not only muscle problems, but also cataract, cardiac anomalies, testicular atrophy, gastrointestinal, and endocrine abnormalities, as well as problems originating in the central nervous system. Ongoing somatic expansion in DM1 patients is thought to contribute to disease progression [6]. …”

Section: Introductionmentioning

confidence: 99%

Transcriptionally Repressive Chromatin Remodelling and CpG Methylation in the Presence of Expanded CTG-Repeats at the DM1 Locus

Brouwer

Huguet

Nicole

et al. 2013

Journal of Nucleic Acids

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An expanded CTG-repeat in the 3′ UTR of the DMPK gene is responsible for myotonic dystrophy type I (DM1). Somatic and intergenerational instability cause the disease to become more severe during life and in subsequent generations. Evidence is accumulating that trinucleotide repeat instability and disease progression involve aberrant chromatin dynamics. We explored the chromatin environment in relation to expanded CTG-repeat tracts in hearts from transgenic mice carrying the DM1 locus with different repeat lengths. Using bisulfite sequencing we detected abundant CpG methylation in the regions flanking the expanded CTG-repeat. CpG methylation was postulated to affect CTCF binding but we found that CTCF binding is not affected by CTG-repeat length in our transgenic mice. We detected significantly decreased DMPK sense and SIX5 transcript expression levels in mice with expanded CTG-repeats. Expression of the DM1 antisense transcript was barely affected by CTG-repeat expansion. In line with altered gene expression, ChIP studies revealed a locally less active chromatin conformation around the expanded CTG-repeat, namely, decreased enrichment of active histone mark H3K9/14Ac and increased H3K9Me3 enrichment (repressive chromatin mark). We also observed binding of PCNA around the repeats, a candidate that could launch chromatin remodelling cascades at expanded repeats, ultimately affecting gene transcription and repeat instability.

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Myotonic dystrophy types 1 and 2

Cited by 61 publications

References 320 publications

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Dynamic changes of nuclear RNA foci in proliferating DM1 cells

Transcriptionally Repressive Chromatin Remodelling and CpG Methylation in the Presence of Expanded CTG-Repeats at the DM1 Locus

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