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Neuromuscular Disorders : NMD Oct 2021Neuromuscular diseases represent an heterogenous group of more than 400 diseases, with a very broad phenotypic spectrum. Given their rarity and complexity, neuromuscular... (Review)
Review
Neuromuscular diseases represent an heterogenous group of more than 400 diseases, with a very broad phenotypic spectrum. Given their rarity and complexity, neuromuscular diseases are often diagnosed with a very significant delay after which irreversible muscle damage may limit the efficacy of treatments when available. In this context, neonatal screening could constitute a solution for early detection and treatment. A systematic review of the literature in PubMed up to May 1, 2021, was conducted according to PRISMA guidelines, including classical neuromuscular diseases and diseases with a clear peripheral nervous system involvement (including central nervous system disease with severe neuropathy). We found seven diseases for which newborn screening data were reported: spinal muscular atrophy (9), Duchenne muscular dystrophy (9), Pompe disease (8), X-linked adrenoleukodystrophy (5), Krabbe disease (4), myotonic dystrophy type 1 (1), metachromatic leukodystrophy (1). The future of newborn screening for neuromuscular disorders pass through a global technological switch, from a biochemical to a genetic-based approach. The rapid development of therapy also requires the possibility to quickly adapt the list of treated conditions, to allow innovative therapies to achieve their best efficacy.
Topics: Glycogen Storage Disease Type II; Humans; Infant, Newborn; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Myotonic Dystrophy; Neonatal Screening; Neuromuscular Diseases
PubMed: 34620514
DOI: 10.1016/j.nmd.2021.07.008 -
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 Molecular... Mar 2022Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.
Topics: Humans; Hypoglycemic Agents; Metformin; Muscle Weakness; Myotonic Dystrophy; Phenotype
PubMed: 35270043
DOI: 10.3390/ijms23052901 -
Neurobiology of Disease Dec 2019Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease showing strong genetic anticipation, and is caused by the expansion of a CTG repeat tract in the 3'-UTR of the... (Review)
Review
Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease showing strong genetic anticipation, and is caused by the expansion of a CTG repeat tract in the 3'-UTR of the DMPK gene. Congenital Myotonic Dystrophy (CDM1) represents the most severe form of the disease, with prenatal onset, symptoms distinct from adult onset DM1, and a high rate of perinatal mortality. CDM1 is usually associated with very large CTG expansions, but this correlation is not absolute and cannot explain the distinct clinical features and the strong bias for maternal transmission. This review focuses upon the molecular and epigenetic factors that modulate disease severity and might be responsible for CDM1. Changes in the epigenetic status of the DM1 locus and in gene expression have recently been observed. Increasing evidence supports a role of a CTCF binding motif as a cis-element, upstream of the DMPK CTG tract, whereby CpG methylation of this site regulates the interaction of the insulator protein CTCF as a modulating trans-factor responsible for the inheritance and expression of CDM1.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Humans; Myotonic Dystrophy; Myotonin-Protein Kinase; Trinucleotide Repeat Expansion
PubMed: 31326502
DOI: 10.1016/j.nbd.2019.104533 -
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 -
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... Nov 2021Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs... (Review)
Review
Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an toxic RNA mechanism, triggered by untranslated CTG and CCTG repeat expansions in the and genes for DM1 and DM2, respectively. Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of both diseases. In this review, we discuss the available information on epigenetic mechanisms that could contribute to the DMs outcome and progression. Changes in DNA cytosine methylation, chromatin remodeling and expression of regulatory noncoding RNAs are described, with the intent of depicting an epigenetic signature of DMs. Epigenetic biomarkers have a strong potential for clinical application since they could be used as targets for therapeutic interventions avoiding changes in DNA sequences. Moreover, understanding their clinical significance may serve as a diagnostic indicator in genetic counselling in order to improve genotype-phenotype correlations in DM patients.
Topics: DNA Methylation; DNA Repeat Expansion; Epigenomics; Genetic Association Studies; Humans; Myotonic Dystrophy; RNA
PubMed: 34830473
DOI: 10.3390/ijms222212594 -
International Journal of Molecular... Nov 2019Myotonic dystrophy involves two types of chronically debilitating rare neuromuscular diseases: type 1 (DM1) and type 2 (DM2). Both share similarities in molecular cause,... (Review)
Review
Myotonic dystrophy involves two types of chronically debilitating rare neuromuscular diseases: type 1 (DM1) and type 2 (DM2). Both share similarities in molecular cause, clinical signs, and symptoms with DM2 patients usually displaying milder phenotypes. It is well documented that key clinical symptoms in DM are associated with a strong mis-regulation of RNA metabolism observed in patient's cells. This mis-regulation is triggered by two leading DM-linked events: the sequestration of Muscleblind-like proteins (MBNL) and the mis-regulation of the CUGBP RNA-Binding Protein Elav-Like Family Member 1 (CELF1) that cause significant alterations to their important functions in RNA processing. It has been suggested that DM1 may be treatable through endogenous modulation of the expression of MBNL and CELF1 proteins. In this study, we analyzed the recent identification of the involvement of microRNA (miRNA) molecules in DM and focus on the modulation of these miRNAs to therapeutically restore normal MBNL or CELF1 function. We also discuss additional prospective miRNA targets, the use of miRNAs as disease biomarkers, and additional promising miRNA-based and miRNA-targeting drug development strategies. This review provides a unifying overview of the dispersed data on miRNA available in the context of DM.
Topics: Alternative Splicing; Animals; CELF1 Protein; Drug Discovery; Gene Expression Regulation; Genetic Therapy; Humans; MicroRNAs; Myotonic Dystrophy; RNA-Binding Proteins
PubMed: 31717488
DOI: 10.3390/ijms20225600 -
Neurology Jan 2021To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1).
METHODS
We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months.
RESULTS
Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants.
CONCLUSIONS
There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months.
Topics: Adult; Cohort Studies; Double-Blind Method; Electrocardiography; Female; Hand Strength; Humans; Male; Mexiletine; Middle Aged; Myotonic Dystrophy; Voltage-Gated Sodium Channel Blockers; Walk Test
PubMed: 33046619
DOI: 10.1212/WNL.0000000000011002