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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 -
Chembiochem : a European Journal of... Sep 2022Small molecule targeting of DNA and RNA sequences has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide...
Small molecule targeting of DNA and RNA sequences has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by RNA gain-of-function. Herein, we report a novel template-selected, reversible assembly of therapeutic agents in situ via aldehyde-amine condensation. Rationally designed small molecule targeting agents functionalized with either an aldehyde or an amine were synthesized and screened against the target nucleic acid sequence. The assembly of fragments was confirmed by MALDI-MS in the presence of DM1-relevant nucleic acid sequences. The resulting hit combinations of aldehyde and amine inhibited the formation of r(CUG) in vitro in a cooperative manner at low micromolar levels and rescued mis-splicing defects in DM1 model cells. This reversible template-selected assembly is a promising approach to achieve cell permeable and multivalent targeting via in situ synthesis and could be applied to other nucleic acid targets.
Topics: Aldehydes; Amines; Base Sequence; DNA; Humans; Ligands; Myotonic Dystrophy; RNA; Trinucleotide Repeat Expansion
PubMed: 35790065
DOI: 10.1002/cbic.202200260 -
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 -
Heart (British Cardiac Society) Dec 2002
Review
Topics: Death, Sudden, Cardiac; Heart Diseases; Humans; Myotonic Dystrophy; Pedigree
PubMed: 12433913
DOI: 10.1136/heart.88.6.665 -
Journal of Neuromuscular Diseases 2018The last literature review on psychopathological features in Myotonic Dystrophy type 1 had been conducted by Ambrosini and Nurnberg in 1979. Since that date, many... (Review)
Review
BACKGROUND
The last literature review on psychopathological features in Myotonic Dystrophy type 1 had been conducted by Ambrosini and Nurnberg in 1979. Since that date, many researches had been carried out.
OBJECTIVE
The aim of this study is (i) to systematically obtain and evaluate the relevant literature on psychopathological features, personality, and coping in individuals with adult phenotypes of Myotonic Dystrophy type 1. (ii) To summarize current research findings and draw conclusions for future research.
METHODS
A systematic search was conducted on Pubmed, PubPsych, PsycInfo, Science Direct, and Scopus covering the period of January 1979 to July 2017.
RESULTS
In view of our literature review, patients show mild psychopathological problems, such as interpersonal difficulties, lack of interest, dysphoria, concern about bodily functioning, and hypersensibility. However, they do not experience more psychiatric disorder in comparison to the general population, except for personality disorders and depression. We discussed problems concerning depression's assessment tool. Patients also present symptoms of several personality disorders: avoidant personality disorder was the most common. Finally, coping strategies relative to limitations resulting from their disease have a negative impact on their quality of life.
CONCLUSIONS
In conclusion, Myotonic Dystrophy type 1 patients did not present homogeneous psychopathological and psychological features. However, based on tendencies observed among Myotonic Dystrophy type 1 patients, elements to conceptualize their social difficulties are provided.
Topics: Adaptation, Psychological; Depression; Humans; Myotonic Dystrophy; Personality; Social Behavior
PubMed: 30040740
DOI: 10.3233/JND-180310 -
Journal of Neuromuscular Diseases 2021The European OPTIMISTIC clinical trial has demonstrated a significant, yet heterogenous effect of Cognitive Behavioural Therapy (CBT) for Myotonic Dystrophy type 1 (DM1)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The European OPTIMISTIC clinical trial has demonstrated a significant, yet heterogenous effect of Cognitive Behavioural Therapy (CBT) for Myotonic Dystrophy type 1 (DM1) patients. One of its remaining aims was the assessment of efficacy and adequacy of clinical outcome measures, including the relatively novel primary trial outcome, the DM1-Activ-c questionnaire.
OBJECTIVES
Assessment of the relationship between the Rasch-built DM1-Activ-c questionnaire and 26 commonly used clinical outcome measurements. Identification of variables associated with CBT response in DM1 patients.
METHODS
Retrospective analysis of the to date largest clinical trial in DM1 (OPTIMISTIC), comprising of 255 genetically confirmed DM1 patients randomized to either standard care or CBT with optionally graded exercise therapy. Correlations of 27 different outcome measures were calculated at baseline (cross-sectional) and of their respective intervention induced changes (longitudinal). Bootstrap enhanced Elastic-Net (BeEN) regression was validated and implemented to select variables associated with CBT response.
RESULTS
In cross-sectional data, DM1-Activ-c correlated significantly with the majority of other outcome measures, including Six Minute Walk Test and Myotonic Dystrophy Health Index. Fewer and weaker significant longitudinal correlations were observed. Nine variables potentially associated with CBT response were identified, including measures of disease severity, executive cognitive functioning and perceived social support.
CONCLUSIONS
The DM1-Activ-c questionnaire appears to be a well suited cross-sectional instrument to assess a variety of clinically relevant dimensions in DM1. Yet, apathy and experienced social support measures were less well captured. CBT response was heterogenous, requiring careful selection of outcome measures for different disease aspects.
Topics: Adult; Cognitive Behavioral Therapy; Cross-Sectional Studies; Exercise Therapy; Female; Humans; Male; Middle Aged; Myotonic Dystrophy; Outcome Assessment, Health Care; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome
PubMed: 34250945
DOI: 10.3233/JND-210634 -
BioMed Research International 2013Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation,... (Review)
Review
Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3'-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.
Topics: 3' Untranslated Regions; Age of Onset; Genetic Testing; Humans; Mutation; Myotonic Dystrophy; Pedigree; Phenotype; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 23586035
DOI: 10.1155/2013/391821