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Journal of the American Heart... Feb 2020Myotonic dystrophy is an inherited systemic disorder affecting skeletal muscle and the heart. Genetic testing for myotonic dystrophy is diagnostic and identifies those... (Review)
Review
Myotonic dystrophy is an inherited systemic disorder affecting skeletal muscle and the heart. Genetic testing for myotonic dystrophy is diagnostic and identifies those at risk for cardiac complications. The 2 major genetic forms of myotonic dystrophy, type 1 and type 2, differ in genetic etiology yet share clinical features. The cardiac management of myotonic dystrophy should include surveillance for arrhythmias and left ventricular dysfunction, both of which occur in progressive manner and contribute to morbidity and mortality. To promote the development of care guidelines for myotonic dystrophy, the Myotonic Foundation solicited the input of care experts and organized the drafting of these recommendations. As a rare disorder, large scale clinical trial data to guide the management of myotonic dystrophy are largely lacking. The following recommendations represent expert consensus opinion from those with experience in the management of myotonic dystrophy, in part supported by literature-based evidence where available.
Topics: Arrhythmias, Cardiac; Cardiologists; Consensus; Heart Disease Risk Factors; Heart Failure; Humans; Myotonic Dystrophy; Practice Patterns, Physicians'; Prognosis; Risk Assessment; Ventricular Dysfunction, Left
PubMed: 32067592
DOI: 10.1161/JAHA.119.014006 -
F1000Research 2018By definition, congenital myopathy typically presents with skeletal muscle weakness and hypotonia at birth. Traditionally, congenital myopathy subtypes have been... (Review)
Review
By definition, congenital myopathy typically presents with skeletal muscle weakness and hypotonia at birth. Traditionally, congenital myopathy subtypes have been predominantly distinguished on the basis of the pathological hallmarks present on skeletal muscle biopsies. Many genes cause congenital myopathies when mutated, and a burst of new causative genes have been identified because of advances in gene sequencing technology. Recent discoveries include extending the disease phenotypes associated with previously identified genes and determining that genes formerly known to cause only dominant disease can also cause recessive disease. The more recently identified congenital myopathy genes account for only a small proportion of patients. Thus, the congenital myopathy genes remaining to be discovered are predicted to be extremely rare causes of disease, which greatly hampers their identification. Significant progress in the provision of molecular diagnoses brings important information and value to patients and their families, such as possible disease prognosis, better disease management, and informed reproductive choice, including carrier screening of parents. Additionally, from accurate genetic knowledge, rational treatment options can be hypothesised and subsequently evaluated and in animal models. A wide range of potential congenital myopathy therapies have been investigated on the basis of improved understanding of disease pathomechanisms, and some therapies are in clinical trials. Although large hurdles remain, promise exists for translating treatment benefits from preclinical models to patients with congenital myopathy, including harnessing proven successes for other genetic diseases.
Topics: Animals; Genetic Testing; Humans; Molecular Diagnostic Techniques; Myotonia Congenita
PubMed: 30631434
DOI: 10.12688/f1000research.16422.1 -
Tidsskrift For Den Norske Laegeforening... Apr 2024Myotonic dystrophy type 1 is an autosomal dominant, inherited multiorgan disorder that can affect people of all ages. It is the most prevalent inherited muscular disease... (Review)
Review
Myotonic dystrophy type 1 is an autosomal dominant, inherited multiorgan disorder that can affect people of all ages. It is the most prevalent inherited muscular disease in adults. Late diagnosis points to limited knowledge among the medical community that symptoms other than typical muscular symptoms can dominate. The condition often worsens with each generation and some families are severely affected. Significantly delayed diagnosis means a risk of more serious development of the disorder and inadequate symptomatic treatment. We hope that this clinical review article may lead to more rapid diagnosis and better follow-up of this patient group.
Topics: Myotonic Dystrophy; Humans; Delayed Diagnosis; Adult
PubMed: 38651711
DOI: 10.4045/tidsskr.23.0687 -
Drug Discovery Today Nov 2017Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene.... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing, and therapeutic gene modulation.
Topics: Animals; Drug Design; Drug Repositioning; Gene Expression Regulation; High-Throughput Screening Assays; Humans; Myotonic Dystrophy; Myotonin-Protein Kinase; Trinucleotide Repeats
PubMed: 28780071
DOI: 10.1016/j.drudis.2017.07.011 -
Current Opinion in Genetics &... Jun 2017Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG... (Review)
Review
Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG triplet repeat in DMPK, whereas DM type 2 is caused by expansion of a CCTG tetramer repeat in CNBP. In both cases the DM mutations lead to expression of dominant-acting RNAs. Studies of RNA toxicity have now revealed novel mechanisms and new therapeutic targets. Preclinical data have suggested that RNA dominance is responsive to therapeutic intervention and that DM therapy can be approached at several different levels. Here we review recent efforts to alleviate RNA toxicity in DM.
Topics: Gene Expression Regulation; Genetic Therapy; Humans; Mutation; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA, Antisense; RNA-Binding Proteins; Trinucleotide Repeat Expansion
PubMed: 28376341
DOI: 10.1016/j.gde.2017.03.007 -
Cortex; a Journal Devoted To the Study... Sep 2021Our ability to interact with those around us plays an important role in our relationships, mental well being and ability to successfully navigate the complex social... (Review)
Review
Our ability to interact with those around us plays an important role in our relationships, mental well being and ability to successfully navigate the complex social society in which we live. Research in social cognitive neuroscience aims to understand the underlying neurobiology of our social behaviours and interactions with others. Myotonic dystrophy type 1 (DM1) is a genetically inherited neuromuscular disorder characterized by mytonia with systemic manifestations such as cardiac disease, respiratory insufficiency, ophthalmic complications, diabetes and frontal balding among others. Individuals with myotonic dystophy have been found to have widespread changes throughout the brain in both grey and white matter territories. They have been noted to experience difficulty with social cognitive function, and to more frequently display atypical personality traits leading to often unrecognized difficulties with everyday life. In this mini review we explore the anatomical basis of social cognition, current techniques for measuring and investigating this impairment including facial emotion recognition and theory of mind. We examine the evidence for general cognitive dysfunction, autism spectrum and personality disorders in DM1. Throughout the review we discuss neuroimaging highlights relevant to social cognition in DM1. Finally, we discuss practical implications relevant to managing people with myotonic dystrophy and highlight future research needs.
Topics: Brain; Cognition; Facial Recognition; Humans; Myotonic Dystrophy; Social Cognition
PubMed: 34154799
DOI: 10.1016/j.cortex.2021.05.004 -
International Journal of Molecular... Aug 2019This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex... (Review)
Review
This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).
Topics: Animals; Humans; Myotonic Dystrophy; RNA, Messenger
PubMed: 31426500
DOI: 10.3390/ijms20164017 -
Revista de Neurologia Jun 2022
Topics: Humans; Myotonic Dystrophy; Thromboembolism
PubMed: 35635364
DOI: 10.33588/rn.7411.2022129 -
International Journal of Molecular... Sep 2022Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of... (Review)
Review
Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: in DM1 and in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients' cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).
Topics: Humans; Myotonic Dystrophy; RNA; RNA Splicing
PubMed: 36142405
DOI: 10.3390/ijms231810491 -
International Journal of Molecular... Jul 2019CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with... (Review)
Review
CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the / gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in . Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients.
Topics: Animals; CRISPR-Cas Systems; Cell- and Tissue-Based Therapy; Gene Editing; Gene Targeting; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genetic Therapy; Humans; Myotonic Dystrophy; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 31357652
DOI: 10.3390/ijms20153689