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Revista de Neurologia Jun 2022
Topics: Humans; Myotonic Dystrophy; Thromboembolism
PubMed: 35635364
DOI: 10.33588/rn.7411.2022129 -
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 -
International Journal of Molecular... Jan 2023Myotonic dystrophy type 1 (DM1) is one of the most common muscular dystrophies and can be potentially treated with antisense therapy decreasing mutant DMPK, targeting... (Review)
Review
Myotonic dystrophy type 1 (DM1) is one of the most common muscular dystrophies and can be potentially treated with antisense therapy decreasing mutant DMPK, targeting miRNAs or their binding sites or via a blocking mechanism for MBNL1 displacement from the repeats. Unconjugated antisense molecules are able to correct the disease phenotype in mouse models, but they show poor muscle penetration upon systemic delivery in DM1 patients. In order to overcome this challenge, research has focused on the improvement of the therapeutic window and biodistribution of antisense therapy using bioconjugation to lipids, cell penetrating peptides or antibodies. Antisense conjugates are able to induce the long-lasting correction of DM1 pathology at both molecular and functional levels and also efficiently penetrate hard-to-reach tissues such as cardiac muscle. Delivery to the CNS at clinically relevant levels remains challenging and the use of alternative administration routes may be necessary to ameliorate some of the symptoms experienced by DM1 patients. With several antisense therapies currently in clinical trials, the outlook for achieving a clinically approved treatment for patients has never looked more promising.
Topics: Mice; Animals; Myotonic Dystrophy; Tissue Distribution; Muscular Dystrophies; Oligonucleotides, Antisense; Myocardium
PubMed: 36769018
DOI: 10.3390/ijms24032697 -
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 -
Child's Nervous System : ChNS :... Apr 2016Ventriculomegaly in infants with congenital myotonic dystrophy (CDM) is common, and the neurosurgical determination of shunting is complex. The natural history of... (Review)
Review
PURPOSE
Ventriculomegaly in infants with congenital myotonic dystrophy (CDM) is common, and the neurosurgical determination of shunting is complex. The natural history of CDM-associated ventriculomegaly from prenatal to natal to postnatal stages is poorly known. The relationship between macrocephaly and ventriculomegaly, incidence of shunt necessity, and early mortality outcomes lack pooled data analysis. This study aims to review clinical features and pathophysiology of CDM, with emphasis on ventriculomegaly progression, ventriculomegaly association with macrocephaly, and incidence of shunting.
METHODS
This is a literature review with pooled data analysis and case report.
RESULTS
One hundred four CDM patients were reviewed in 13 articles that mentioned CDM with ventriculomegaly and/or head circumference. Data was very limited: only 7 patients had data on the presence or absence of prenatal ventriculomegaly, 97 on ventriculomegaly at birth, and 32 on whether or not the ventricles enlarged post-natally. Three patients of 7 (43 %) had pre-natally diagnosed ventriculomegaly, 43 of 97 (44 %) had ventriculomegaly at birth, and only 5 of 32 (16 %) had progressive enlargement of ventricles post-natally. Only 5 of 104 patients had a documented shunt placement: 1 for obstructive, 1 for a post-hemorrhagic communicating, 2 for a communicating hydrocephalus without hemorrhage, and 1 with unknown indication. Of 13 macrocephalic patients with data about ventricular size, 12 had ventriculomegaly.
CONCLUSIONS
Ventriculomegaly occurs regularly with CDM but most often does not require CSF diversion. Decisions regarding neurosurgical intervention will necessarily be based on limited information, but shunting should only occur once dynamic data confirms hydrocephalus.
Topics: Cerebrospinal Fluid Shunts; Humans; Hydrocephalus; Myotonic Dystrophy; Pediatrics
PubMed: 26747623
DOI: 10.1007/s00381-015-2993-y -
Heart Rhythm Mar 2022Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy, presenting with a constellation of systemic findings secondary to a CTG triplet... (Review)
Review
Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy, presenting with a constellation of systemic findings secondary to a CTG triplet expansion of the noncoding region of the DMPK gene. Cardiac involvement is frequent, with conduction disease and supraventricular and ventricular arrhythmias being the most prevalent cardiac manifestations, often developing from a young age. The development of cardiac arrhythmias has been linked to increased morbidity and mortality, with sudden cardiac death well described. Strategies to mitigate risk of arrhythmic death have been developed. In this review, we outline the current knowledge on the pathophysiology of rhythm abnormalities in patients with myotonic dystrophy and summarize available knowledge on arrhythmic risk stratification. We also review management strategies from an electrophysiological perspective, attempting to underline the substantial unmet need to address residual arrhythmic risks for this population.
Topics: Adult; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Humans; Myotonic Dystrophy
PubMed: 34843968
DOI: 10.1016/j.hrthm.2021.11.028 -
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 -
Nature Reviews. Neurology Sep 2023
Topics: Humans; Myotonic Dystrophy; Muscle Development
PubMed: 37553392
DOI: 10.1038/s41582-023-00862-7 -
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 -
European Heart Journal Aug 2014
Topics: Female; Heart Diseases; Humans; Male; Myotonic Dystrophy
PubMed: 24935921
DOI: 10.1093/eurheartj/ehu199