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Continuum (Minneapolis, Minn.) Dec 2022Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are genetic disorders affecting skeletal and smooth muscle, heart, brain, eyes, and other organs. The... (Review)
Review
PURPOSE OF REVIEW
Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are genetic disorders affecting skeletal and smooth muscle, heart, brain, eyes, and other organs. The multisystem involvement and disease variability of myotonic dystrophy have presented challenges for clinical care and research. This article focuses on the diagnosis and management of the disease. In addition, recent advances in characterizing the diverse clinical manifestations and variability of the disease are discussed.
RECENT FINDINGS
Studies of the multisystem involvement of myotonic dystrophy, including the most lethal cardiac and respiratory manifestations and their molecular underpinnings, expand our understanding of the myotonic dystrophy phenotype. Advances have been made in understanding the molecular mechanisms of both types of myotonic dystrophy, providing opportunities for developing targeted therapeutics, some of which have entered clinical trials in DM1.
SUMMARY
Continued efforts focus on advancing our molecular and clinical understanding of DM1 and DM2. Accurately measuring and monitoring the diverse and variable clinical manifestations of myotonic dystrophy in clinic and in research is important to provide adequate care, prevent complications, and find treatments that improve symptoms and life quality.
Topics: Humans; Myotonic Dystrophy; Phenotype; Brain
PubMed: 36537977
DOI: 10.1212/CON.0000000000001184 -
Acta Myologica : Myopathies and... Dec 2020The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy. Phenotypes of DM1 and DM2 are similar, but there are some important differences,... (Review)
Review
The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy. Phenotypes of DM1 and DM2 are similar, but there are some important differences, including the presence or absence of congenital form, muscles primarily affected (distal vs proximal), involved muscle fiber types (type 1 vs type 2 fibers), and some associated multisystemic phenotypes. There is currently no cure for the myotonic dystrophies but effective management significantly reduces the morbidity and mortality of patients. For the enormous understanding of the molecular pathogenesis of myotonic dystrophy type 1 and myotonic dystrophy type 2, these diseases are now called "spliceopathies" and are mediated by a primary disorder of RNA rather than proteins. Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies. Gene therapy for myotonic dystrophy type 1 and myotonic dystrophy type 2 appears to be very close and the near future is an exciting time for clinicians and patients.
Topics: Humans; Microsatellite Repeats; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA-Binding Proteins
PubMed: 33458578
DOI: 10.36185/2532-1900-026 -
Neurologia Apr 2020Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of...
BACKGROUND AND OBJECTIVES
Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1.
MATERIAL AND METHODS
Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide.
RECOMMENDATIONS
The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives.
CONCLUSION
MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.
Topics: Deglutition Disorders; Follow-Up Studies; Genetic Counseling; Humans; Myotonic Dystrophy; Practice Guidelines as Topic
PubMed: 31003788
DOI: 10.1016/j.nrl.2019.01.001 -
Drug Discovery Today Mar 2023The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs... (Review)
Review
The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation. Furthermore, newly disclosed promising preclinical data for several additional nucleic-acid therapeutic candidates and a CRISPR-based approach, as well as the advent into the pipeline of novel therapeutic programs, increase the plausibility of success in the demanding task of providing valid treatments to patients with DM1.
Topics: Humans; Myotonic Dystrophy; Drug Development
PubMed: 36634841
DOI: 10.1016/j.drudis.2023.103489 -
The Lancet. Neurology Mar 2023Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA.
METHODS
In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete.
FINDINGS
Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose.
INTERPRETATION
Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed.
FUNDING
Ionis Pharmaceuticals, Biogen.
Topics: Adult; Humans; Double-Blind Method; Myotonic Dystrophy; Myotonin-Protein Kinase; Oligonucleotides, Antisense; RNA; RNA, Messenger; Treatment Outcome
PubMed: 36804094
DOI: 10.1016/S1474-4422(23)00001-7 -
Semergen Oct 2020
Topics: Follow-Up Studies; Humans; Myotonic Dystrophy; Plant Extracts; Primary Health Care
PubMed: 33039262
DOI: 10.1016/j.semerg.2020.09.001 -
Genes Feb 2022Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and... (Review)
Review
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), both dominantly inherited with significant overlap in clinical manifestations. DM1 results from CTG repeat expansions in the 3'-untranslated region (3'UTR) of the (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2 is caused by CCTG repeat expansions in intron 1 of the (cellular nucleic acid-binding protein) gene on chromosome 3. Recent advances in genetics and molecular biology, especially in the field of RNA biology, have allowed better understanding of the potential pathomechanisms involved in DM. In this review article, core clinical features and genetics of DM are presented followed by a discussion on the current postulated pathomechanisms and therapeutic approaches used in DM, including the ones currently in human clinical trial phase.
Topics: 3' Untranslated Regions; Brain; Heart; Humans; Myotonic Dystrophy
PubMed: 35205411
DOI: 10.3390/genes13020367 -
Continuum (Minneapolis, Minn.) Dec 2019This article describes the clinical features, pathogenesis, prevalence, diagnosis, and management of myotonic dystrophy type 1 and myotonic dystrophy type 2. (Review)
Review
PURPOSE OF REVIEW
This article describes the clinical features, pathogenesis, prevalence, diagnosis, and management of myotonic dystrophy type 1 and myotonic dystrophy type 2.
RECENT FINDINGS
The prevalence of myotonic dystrophy type 1 is better understood than the prevalence of myotonic dystrophy type 2, and new evidence indicates that the risk of cancer is increased in patients with the myotonic dystrophies. In addition, descriptions of the clinical symptoms and relative risks of comorbidities such as cardiac arrhythmias associated with myotonic dystrophy type 1 have been improved.
SUMMARY
Myotonic dystrophy type 1 and myotonic dystrophy type 2 are both characterized by progressive muscle weakness, early-onset cataracts, and myotonia. However, both disorders have multisystem manifestations that require a comprehensive management plan. While no disease-modifying therapies have yet been identified, advances in therapeutic development have a promising future.
Topics: Adult; Female; Humans; Infant, Newborn; Male; Middle Aged; Myotonic Dystrophy
PubMed: 31794466
DOI: 10.1212/CON.0000000000000793 -
Muscle & Nerve Sep 2022
Topics: Humans; Monitoring, Physiologic; Myotonic Dystrophy; Neuromuscular Diseases; Neuromuscular Nondepolarizing Agents
PubMed: 35674416
DOI: 10.1002/mus.27658 -
International Journal of Molecular... Feb 2022Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye.... (Review)
Review
Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by expanded CTG and CCTG repeats, respectively. In both forms, the mutant transcripts containing expanded repeats aggregate as nuclear foci and sequester several RNA-binding proteins, resulting in alternative splicing dysregulation. Although certain alternative splicing events are linked to the clinical DM phenotypes, the molecular mechanisms underlying multiple DM symptoms remain unclear. Interestingly, multi-systemic DM manifestations, including muscle weakness, cognitive impairment, cataract, and frontal baldness, resemble premature aging. Furthermore, cellular senescence, a critical contributor to aging, is suggested to play a key role in DM cellular pathophysiology. In particular, several senescence inducers including telomere shortening, mitochondrial dysfunction, and oxidative stress and senescence biomarkers such as cell cycle inhibitors, senescence-associated secretory phenotype, chromatin reorganization, and microRNA have been implicated in DM pathogenesis. In this review, we focus on the clinical similarities between DM and aging, and summarize the involvement of cellular senescence in DM and the potential application of anti-aging DM therapies.
Topics: Alternative Splicing; Cellular Senescence; Humans; Muscle, Skeletal; Myotonic Dystrophy; RNA-Binding Proteins
PubMed: 35216455
DOI: 10.3390/ijms23042339