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Journal of Clinical Sleep Medicine :... Dec 2021Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is...
STUDY OBJECTIVES
Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is no consensus on the sleep protocols to be used, assessments vary, and only a minority of patients are regularly tested or are on treatment for EDS. Our study presents data on self-reported and objective EDS in adult-onset myotonic dystrophy type 1.
METHODS
Sixty-three patients with adult-onset DM1 were subjected to EDS-sleep assessments (polysomnography, Multiple Sleep Latency Test, Epworth Sleepiness Scale). Correlation coefficients were computed to assess the relationship between sleep and sleepiness test results, fatigue, and quality of life.
RESULTS
33% and 48% of patients had EDS based, respectively, on the Epworth Sleepiness Scale and the Multiple Sleep Latency Test, with a low concordance between these tests (k = 0.19). Thirteen patients (20%) displayed 2 or more sleep-onset rapid eye movement periods on Multiple Sleep Latency Test. Patients having EDS by Multiple Sleep Latency Test had a shorter disease duration ( < .05), higher total sleep time and sleep efficiency and lower wake after sleep onset on polysomnography. Patients with self-reported EDS reported significantly higher fatigue score compared with patients without EDS ( < .05). No other difference was found in demographic, clinical, and respiratory features.
CONCLUSIONS
EDS test results are contradictory, making treatment options difficult. Combining quantitative tests and self-reported scales may facilitate physicians in planning EDS care with patients and families.
CITATION
Sansone VA, Proserpio P, Mauro L, et al. Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1. . 2021;17(12):2383-2391.
Topics: Adult; Disorders of Excessive Somnolence; Humans; Myotonic Dystrophy; Polysomnography; Quality of Life; Self Report
PubMed: 34170223
DOI: 10.5664/jcsm.9438 -
The Journal of Clinical Endocrinology... Sep 2021Myotonic dystrophy is a dominantly inherited multisystem disorder that results from increased CTG repeats in the 3' region of the myotonic dystrophy protein kinase gene... (Review)
Review
Myotonic dystrophy is a dominantly inherited multisystem disorder that results from increased CTG repeats in the 3' region of the myotonic dystrophy protein kinase gene (DMPK). The mutant DMPK mRNA remains in the nucleus and sequesters RNA-binding proteins, including regulators of mRNA splicing. Myotonic dystrophy is characterized by a highly variable phenotype that includes muscle weakness and myotonia, and the disorder may affect the function of many endocrine glands. DMPK mRNA is expressed in muscle, testis, liver, pituitary, thyroid, and bone; the mutated form leads to disruption of meiosis and an increase in fetal insulin receptor-A relative to adult insulin receptor-B, resulting in adult primary testicular failure and insulin resistance predisposing to diabetes, respectively. Patients with myotonic dystrophy are also at increased risk for hyperlipidemia, nonalcoholic fatty liver disease, erectile dysfunction, benign and malignant thyroid nodules, bone fractures, miscarriage, preterm delivery, and failed labor during delivery. Circulating parathyroid hormone and adrenocorticotropic hormone levels may be elevated, but the mechanisms for these associations are unclear. This review summarizes what is known about endocrine dysfunction in individuals with myotonic dystrophy.
Topics: Endocrine System; Endocrine System Diseases; Female; Humans; Male; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA, Messenger; RNA-Binding Proteins
PubMed: 34125228
DOI: 10.1210/clinem/dgab430 -
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 -
Neuroepidemiology 2022Myotonic dystrophy (DM), the most common muscular dystrophy in adults, is a group of autosomal inherited neuromuscular disorders characterized by progressive muscle... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Myotonic dystrophy (DM), the most common muscular dystrophy in adults, is a group of autosomal inherited neuromuscular disorders characterized by progressive muscle weakness, myotonia, and cardiac conduction abnormalities. Due to the different gene mutations, DM has been subclassified into DM type 1 (DM1) and type 2 (DM2). However, the prevalence studies on DM and its subtypes are insufficient.
METHODS
The PubMed (1966-2022), MEDLINE (1950-2022), Web of Science (1864-2022), and Cochrane Library (2022) databases were searched for original research articles published in English. The quality of the included studies was assessed by a checklist adapted from Strengthening the Reporting of Observational studies in Epidemiology. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random-effects model. Heterogeneity was assessed using the Cochrane Q statistic and the I2 statistic.
RESULTS
A total of 17 studies were included in the systematic review and meta-analysis. Of the 17 studies evaluated, 14 studies were considered medium quality, 2 studies were considered high quality, and 1 study was considered low quality. The global prevalence of DM varied widely from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM was 9.99 cases (95% CI: 5.62-15.53) per 100,000. The pooled estimate of the prevalence of DM1 was 9.27 cases (95% CI: 4.73-15.21) per 100,000, ranging from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM2 was 2.29 cases (95% CI: 0.17-6.53) per 100,000, ranging from 0.00 to 24.00 cases per 100,000.
CONCLUSION
Our study provided accurate estimates of the prevalence of DM. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher quality studies on orphan diseases.
Topics: Adult; Humans; Myotonic Dystrophy; Prevalence
PubMed: 35483324
DOI: 10.1159/000524734 -
Muscle & Nerve Oct 2022Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM...
INTRODUCTION/AIMS
Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM type 1 (DM1), but it is unknown whether this applies uniformly to all features. We compared the age-dependent risk for milestone events in DM1 and DM2 and tested for associations with age of onset and sex.
METHODS
We studied a large cohort of adult participants in a national registry of DM1 and DM2. Using annual surveys from participants, we ascertained milestone events for motor involvement (use of cane, walker, ankle brace, wheelchair, or ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of employment due to DM, and death.
RESULTS
Mean follow-up of registry participants (929 DM1 and 222 DM2 patients) was 7 years. Disability and motor milestones occurred at earlier ages in DM1 than in DM2. In contrast, the risk of diabetes was higher and tended to occur earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events tended to occur earlier, and life expectancy was reduced, when symptoms began at younger ages. In DM1, men were at greater risk for disability (HR, 1.34; P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2; P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68; P = .001) or malignancy (HR, 0.66; P ≤ .01).
DISCUSSION
Milestone events recorded through registries can be used to assess long-term impact of DM in large cohorts. Except for diabetes, the age-related risk of milestone events is greater in DM1 than in DM2.
Topics: Adult; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Male; Myotonic Dystrophy; Registries
PubMed: 35778789
DOI: 10.1002/mus.27674 -
Neuromuscular Disorders : NMD Aug 2021Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystemic disorder caused by CCTG repeats expansion in the first intron of the CNBP gene. In this review we... (Review)
Review
Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystemic disorder caused by CCTG repeats expansion in the first intron of the CNBP gene. In this review we focus on the brain involvement in DM2, including its pathogenic mechanisms, microstructural, macrostructural and functional brain changes, as well as the effects of all these impairments on patients' everyday life. We also try to understand how brain abnormalities in DM2 should be adequately measured and potentially treated. The most important pathogenetic mechanisms in DM2 are RNA gain-of-function and repeat-associated non-ATG (RAN) translation. One of the main neuroimaging findings in DM2 is the presence of diffuse periventricular white matter hyperintensity lesions (WMHLs). Brain atrophy has been described in DM2 patients, but it is not clear if it is mostly caused by a decrease of the white or gray matter volume. The most commonly reported specific cognitive symptoms in DM2 are dysexecutive syndrome, visuospatial and memory impairments. Fatigue, sleep-related disorders and pain are also frequent in DM2. The majority of key symptoms and signs in DM2 has a great influence on patients' daily lives, their psychological status, economic situation and quality of life.
Topics: Atrophy; Brain; Gray Matter; Humans; Magnetic Resonance Imaging; Myotonic Dystrophy; Quality of Life
PubMed: 34244019
DOI: 10.1016/j.nmd.2021.06.002 -
International Journal of Molecular... Sep 2019Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and... (Review)
Review
Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by RNA-binding proteins. CircRNAs are abundant across eukaryotes; however, their biological functions remain largely speculative. Recently, they have been emerging as new members of a gene regulatory network and contributing factors in various human diseases including cancer, neurological, muscular and cardiovascular disorders. In this review, we present an overview of the current knowledge about circRNAs biogenesis and their aberrant expression in various human disorders. In particular, we focus on the latest discovery of circRNAs global upregulation in myotonic dystrophy type 1 (DM1) skeletal muscles and the role these prospective biomarkers might have for prognosis and therapeutic response in DM1.
Topics: Alternative Splicing; Animals; Biomarkers; Disease Susceptibility; Gene Expression Regulation; Humans; Myotonic Dystrophy; RNA, Circular; RNA-Binding Proteins
PubMed: 31500099
DOI: 10.3390/ijms20184385 -
International Journal of Molecular... Nov 2021Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth... (Review)
Review
Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.
Topics: Animals; Humans; Muscles; Myotonic Dystrophy
PubMed: 34769305
DOI: 10.3390/ijms222111874 -
International Journal of Molecular... Dec 2021Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide... (Review)
Review
Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA.
Topics: Cell Nucleus; Gene Regulatory Networks; Humans; Myotonic Dystrophy; RNA Stability; RNA, Messenger; Trinucleotide Repeat Expansion
PubMed: 34948025
DOI: 10.3390/ijms222413225