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Myotonic dystrophy type 1 (DM1) is a serious multisystem disorder caused by GCA repeat expansions in the DMPK gene. Early and accurate diagnosis, often requiring reliable DNA-diagnostic techniques, is critical for preventing life-threatening cardiac complications. Clinically, two main diagnostic challenges exist. Firstly, because of overlapping symptomatology with other conditions, conventional DNA-testing methods focusing on DM1 expansion detection ensure diagnostic results only in a small subset of patients, and frequently, further DNA-testing in remaining cases is necessary. Secondly, because of variable symptomatology and age of onset, not all DM1 patients are referred for DM1 genetic testing, leading to unrecognized but at-risk cases. When using conventional methods, the main technical problems are expanded-allele sizing and sensitivity to the presence of sequence interruptions. On a set of 50 individual genomes, including ten DM1 patients, we tested the performance of short-read whole-genome sequencing (WGS), one of the most up-to-date molecular testing methods. We identified all expansion-range DM1 alleles and characterized sequence interruptions in seven expansion-range/premutation-range alleles. Although neither the tested conventional methods, nor WGS allowed expanded-allele sizing, conventional methods provided higher sizing limits for normal-range alleles. Genotyping concordance rate was found to be 95-99 %. WGS was found to be superior in elucidating the sequence structure of the motifs, even if they fall outside the sizing limit (from partial reads). In addition, WGS enables the identification of genetic modifiers in other genes and the detection of alternative diagnoses in DM1-negative patients by extension of the bioinformatic evaluation of the generated data., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tomas Szemes reports a relationship with Genovisio Ltd. that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Myotonic dystrophy type 1 (DM1) is considered a progeroid disease (i.e., causing premature aging). This hypervariable disease affects multiple systems, such as the musculoskeletal, central nervous, gastrointestinal, and others. Despite advances in understanding the underlying pathogenic mechanism of DM1, numerous gaps persist in our understanding, hindering elucidation of the heterogeneity and severity of its symptoms. Accumulating evidence indicates that the toxic intracellular RNA accumulation associated with DM1 triggers cellular senescence. These cells are in a state of irreversible cell cycle arrest and secrete a cocktail of cytokines, referred to as a senescence-associated secretory phenotype (SASP), that can have harmful effects on neighboring cells and more broadly. We hypothesize that cellular senescence contributes to the pathophysiology of DM1, and clearance of senescent cells is a promising therapeutic approach for DM1. We will discuss the therapeutic potential of different senotherapeutic drugs, especially senolytics that eliminate senescent cells, and senomorphics that reduce SASP expression., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)

Repeat expansion disorders, exemplified by myotonic dystrophy type 1 (DM1), present challenges in diagnostic quantification because of the variability and complexity of repeat lengths. Traditional diagnostic methods, including PCR and Southern blotting, exhibit limitations in sensitivity and specificity, necessitating the development of innovative approaches for precise and rapid diagnosis. Here, we introduce a CRISPR-based diagnostic method, REPLICA ( re peat- p rimed l ocating of i nherited disease by Ca s3), for the quantification and rapid diagnosis of DM1. This method, using in vitro-assembled CRISPR-Cas3, demonstrates superior sensitivity and specificity in quantifying CTG repeat expansion lengths, correlated with disease severity. We also validate the robustness and accuracy of CRISPR diagnostics in quantitatively diagnosing DM1 using patient genomes. Furthermore, we optimize a REPLICA-based assay for point-of-care-testing using lateral flow test strips, facilitating rapid screening and detection. In summary, REPLICA-based CRISPR diagnostics offer precise and rapid detection of repeat expansion disorders, promising personalized treatment strategies.

Myotonic dystrophy type 1 (DM1) is a dominantly inherited multi-system disease caused by expanded CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Similar to other repeat disorders, the expanded trinucleotide repeat is unstable and demonstrates a tendency to increase repeat size with age in affected tissues. DNA mismatch repair system is implicated in somatic instability. It has been demonstrated that DM1 patient-derived induced pluripotent stem cells (DM1-iPSCs) show repeat instability, in which involvement of mismatch repair proteins has been suggested. Here we identified ZNF850 as a novel CTG repeat expansion-related molecule in DM1-iPSCs. ZNF850 was downregulated in a DM1-iPSC clone whose CTG repeat is exceptionally stable. We found that RNAi-mediated ZNF850 downregulation in DM1-iPSCs significantly reduced the repeat expansion and resulting instability. In adult skeletal muscle tissue of DM1 patients, ZNF850 expression levels were positively correlated with the repeat size. Furthermore, we found that ZNF850 protein can bind to the expanded CTG repeat sequence, and is located in proximity to MutSβ components. These results suggest that ZNF850 might play a role in repeat instability in DM1 by recruiting MutSβ to the repeat sequence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSA LR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK-8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK-8722 improves alternative splicing toward wild-type levels in male and female HSA LR muscle. However, the effects of MK-8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK-8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK-8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK-8722 and AICAR triggered the rapid and transient increase in phospho-AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK-8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model., Methods: ECG parameters were evaluated at baseline and post flecainide challenge. Calcium transient and action potential parameters were evaluated in Langendorff-perfused hearts using fluorescence optical mapping. Calcium transient/sparks were evaluated in ventricular myocytes via confocal microscopy. Protein and mRNA levels for calcium handling proteins were evaluated using western blot and RT-qPCR, respectively., Results: DMSXL mice showed arrhythmic events on ECG including premature ventricular contractions and sinus block. DMSXL mice showed increased calcium transient time to peak without any change to voltage parameters. Calcium alternans and both sustained and non-sustained ventricular tachyarrhythmias were readily inducible in DMSXL mice. The confocal experiments also showed calcium transient alternans and increased frequency of calcium sparks in DMSXL cardiomyocytes. These calcium abnormalities were correlated with increased RyR2 phosphorylation without changes to the other calcium handling proteins., Conclusions: The DMSXL mouse model of DM1 exhibited enhanced arrhythmogenicity associated with abnormal intracellular calcium handling due to hyperphosphorylation of RyR2, pointing to RyR2 as a potential new therapeutic target in DM1 treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction/aims: Hypogammaglobulinemia is a common yet under-recognized feature of myotonic dystrophy type 1 (DM1). The aims of our study were to determine the frequency of immunoglobulin G (IgG) deficiency in our cohort, to examine the association between immunoglobulin levels and cytosine-thymine-guanine (CTG) repeat length in the DMPK gene, and to assess whether IgG levels are associated with an increased risk of infection in DM1 patients., Methods: We conducted a single-center, retrospective cross-sectional study of 65 adult patients with DM1 who presented to the Neuromuscular Clinic at Concord Repatriation General Hospital, Sydney, Australia, between January 2002 and January 2022. We systematically collected and analyzed clinical, laboratory, and genetic data for all patients with available serum electrophoresis and/or IgG level results., Results: Forty-one percent of DM1 patients had IgG deficiency despite normal lymphocyte counts, IgA, IgM, and albumin levels. There was an association between CTG repeat expansion size and the degree of IgG deficiency (F = 6.3, p = .02). There was no association between IgG deficiency and frequency of infection in this group (p = .428)., Discussion: IgG deficiency is a frequent occurrence in DM1 patients and is associated with CTG repeat expansion size. Whether hypogammaglobulinemia is associated with increased infection risk in DM1 is unclear. A prospective multicenter cohort study is needed to evaluate this., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Muscle dystrophy type 1 is the most common form of muscular dystrophy and is characterized by progressive distal dominant muscle weakness, muscle atrophy, and myotonic phenomena. Patients with progressive neuromuscular diseases such as myotonic dystrophy type 1 are prone to muscle weakness, movement disorders, and fatigue due to their underlying disease, which may limit their physical activity and ambulation. Six courses of gait training with a hybrid assistive limb (HAL) were performed in an adult male with myotonic dystrophy type 1 over 4.5 years. The two-minute walking distance and knee joint strength tended to increase, and the Timed Up and Go test time tended to decrease with gait training with HAL before and after each intervention. In the long term, the two-minute walking distance decreased slowly, but the Timed Up and Go and knee joint strength tended to be maintained. Functional ambulation category and activities of daily living levels were also maintained. These results suggest that intermittent gait training may be an effective rehabilitation method for maintaining gait independence and activities of daily living in patients with myotonic dystrophy type 1. The frequency and number of interventions should be considered for further effectiveness., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of the Ibaraki Prefectural University of Health Sciences issued approval 1056. This study was conducted in accordance with the Declaration of Helsinki. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nakazawa et al.)

Myotonic dystrophy type 1 (DM1) is a heterogeneous neuromuscular disorder characterized by progressive muscle weakness and myotonia. This study investigates the progression of muscular strength and function over a four-year period. Patients with DM1 were examined at baseline and four years later. The following metrics were assessed over time: muscle strength (Medical Research Council-sumscore), hand-grip strength (Martin-Vigorimeter), hand-grip relaxation time (myotonia), and limitations in activities of daily living and (DM1Activ C questionnaire). A total of 648 patients entered the registry. Recruitment and follow-up is ongoing. In our manuscript, we focus on, 187 patients who were followed for 4 years. A significant decline in MRC sum score was observed, with distal muscles showing more deterioration. Hand-grip strength decreased significantly, with notable differences between sex and phenotype classified by disease onset. Surprisingly, an improvement of myotonia was observed. Follow-up analysis revealed a significant interaction between myotonia and grip-strength over time. Thus, the improvement in myotonia is likely explained by decreased in grip strength. Finally, there was a significant reduction in DM1Activ C score, indicating decreased activity and social participation. This study demonstrated variability in disease progression depending on sex, phenotype and disease status. This research demonstrates a nuanced pattern of disease progression, highlighting the need to combine different outcome measures to fully understand the complexity of DM1., Competing Interests: Declaration of competing interest L. la Fontaine reports no competing interests. J. Bruijnes reports no competing interests. F. Smulders reports no competing interests. C. Gorissen-Brouwers reports no competing interests. I. Karnebeek reports no competing interests. H. Braakman reports no competing interests. S. Klinkenberg reports no competing interests. K. Mul conducted consultancy services for Avidity Biosciences. All reimbursements were received by Radboudumc. Dr. Mul did not personally benefit financially from these activities. P ‘t Hoen received grants from the ZonMW foundation. All reimbursements were received by the Radboud university medical center. P. ‘t Hoen did not personally benefit financially from these activities. S. van Kuijk reports no competing interests. B. van Engelen received grants from the Prinses Beatrix Spierfonds. Consultancy services for Fulcrum, Avidity, Dyne, and Arrowhead. All reimbursements were received by Radboudumc. B van Engelen did not personally benefit from these activities. I. Merkies received grants from Grifols and Lamepro. Consultancy services for Talecris, CSL, Behring, Novartis, Octafarma, UCB and Argenx. I. Merkies did not personally benefit financially from these activities. C. Faber received grants from the Prinses Beatrix Spierfonds. Consultancy services for Biogen, Vertex, Olipass, and Sangamo. All reimbursements were received by MUMC+. C. Faber did not personally benefit financially from these activities., (Copyright © 2024. Published by Elsevier B.V.)

Here, we present an autopsy case of long-standing myotonic dystrophy type 1 (DM1) in a patient who developed a pancreatic intraductal papillary mucinous neoplasm (IPMN). DM1 is a progressive genetic disorder that affects multiple organs, including the respiratory muscles. Several nationwide registry-based cohort studies have suggested that patients with DM1 have an increased risk of developing pancreatic cancers such as pancreatic ductal adenocarcinoma (PDAC). Pancreatic IPMNs are thought to progress from benign neoplasms to invasive cancers, and surgical specimens are usually required for the pathological diagnosis of pancreatic IPMNs. Although certain risk factors for developing pancreatic IPMNs reportedly overlap with those for PDAC, few cases of DM1 with pancreatic IPMNs have been reported. This is partly because pancreatectomy is associated with relatively high morbidity and mortality rates and few patients with DM1 who are suspected of having pancreatic IPMNs are candidates for surgical resection. Therefore, cases of DM1 with histopathologically diagnosed pancreatic IPMNs are rare, and the accumulation of such cases is important for understanding the association between DM1 and pancreatic IPMNs., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This work was supported by JSPS KAKENHI Grant Number JP23K14495 and the Smoking Research Foundation. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nonaka et al.)

Myotonic dystrophy Type 1 (DM1) is a neuromuscular disease characterized by multisystemic involvement including a progressive loss of muscle mass and strength. Further investigation on the effect of exercise in adults with DM1 is needed to incorporate impactful recent findings to better understand the utility of exercise as an intervention. This review aims to summarize and appraise the literature on the effects of aerobic and strength training on clinical and physiological variables in adults with DM1. Six online databases (PubMed, Scopus, Web of Science, CINAHL, EMBASE, and CENTRAL) will be searched using appropriate search terms. Two reviewers will independently screen the relevant studies and extract the data from the selected articles. The methodological quality of the studies included will be assessed using the Joanna Briggs Critical Appraisal checklist. A meta-analysis will be performed if appropriate. This systematic review and meta-analysis will summarize, synthesize, and appraise evidence on the effect of aerobic and strength training on clinical and physiological variables in adults with DM1. The findings of this review will help in clinical decision-making and guide future researchers working with this patient population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Introduction: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease characterized by myotonia and progressive muscular weakness and atrophy. The aim of this study was to investigate the usefulness of longitudinal muscle MRI in detecting disease activity and progression in DM1, and to better characterize muscle edema, fat replacement and atrophy overtime., Materials and Methods: This is a prospective, observational, longitudinal study including 25 DM1 patients that performed at least two muscle MRIs. Demographic and genetic characteristics were recorded. Muscular Impairment Rating Scale (MIRS) and MRC score were performed within 3 months from MRIs at baseline (BL) and at follow-up (FU). We analysed 32 muscles of lower body (LB) and 17 muscles of upper body (UB) by T1 and STIR sequences. T1-, STIR- and atrophy scores and their variations were evaluated. Correlations between MRIs' scores and demographic, clinical and genetic characteristics were analysed., Results: Eighty (80%) of patients showed fat replacement progression at FU. The median T1 score progression (ΔT1-score) was 1.3% per year in LB and 0.5% per year in UB. The rate of fat replacement progression was not homogenous, stratifying patients from non-progressors to fast progressors (> 3% ΔT1-score per year). Half of the STIR-positive muscles at BL showed T1-score progression at FU. Two patients with normal MRI at baseline only showed STIR-positive muscle at FU, marking the disease activity onset. STIR positivity at baseline correlated with fat replacement progression (ΔT1-score; p < 0.0001) and clinical worsening at FU (ΔMRC-score; p < 0.0001). Sixty-five (65%) of patients showed STIR- and fat replacement-independent muscle atrophy progression, more evident in UB., Conclusions: Muscle MRI represents a sensitive biomarker of disease activity, severity, and progression in DM1. STIR alterations precede fat replacement and identify patients with a higher risk of disease progression, while T1-sequences reveal atrophy and fat replacement progression before clinical worsening., (© 2024. The Author(s).)

Myotonic dystrophy type 1 is an autosomal dominant condition due to a CTG repeat expansion in the myotonic dystrophy protein kinase (DMPK) gene. This multisystem disorder affects multiple organ systems. Hypogonadism in males affected by myotonic dystrophy is commonly reported; however, the effect on female hypogonadism remains controversial. A 19-year-old female was referred to our genetics clinic due to primary amenorrhea without any family history of similar symptoms. Initial genetics evaluation identified a variant of uncertain significance in IGSF10, c.2210T>C (p.Phe737Ser). Follow-up genetic evaluation via whole genome sequencing identified at least 100 CTG repeats in the DMPK gene, thus resulting in the diagnosis of myotonic dystrophy type 1. The patient remains otherwise asymptomatic from myotonic dystrophy. This is the first report that demonstrates primary amenorrhea as a possible presenting feature of myotonic dystrophy type 1, thus providing evidence supporting female hypogonadism in myotonic dystrophy type 1., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Myotonic dystrophy is a hereditary neurological disease. While cardiovascular complications have been recognized, recent reports indicate that it increases the risk of deep vein thrombosis and pulmonary embolism (DVT/PE) compared to other dystrophies and healthy individuals with dyspraxia and a history of DVT as risk factors. It is important to consider myotonic dystrophy in patients with repeated idiopathic DVT/PE and to provide appropriate medical consultation., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2024 The Author(s). Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Background and Objective : Although extracorporeal membrane oxygenation (ECMO) is an essential life-saving technique for patients with refractory cardiopulmonary shock, it can be fatal in certain cases. Case Presentation : A 19-year-old girl treated with ECMO presented with acute limb ischemia 2 days after cannula removal. The decannulation was performed percutaneously by an interventional cardiologist, and the vascular surgery department was consulted after the patient developed symptoms. The first suspected diagnosis was thrombosis due to incorrect use of the closure device. However, the artery had ruptured due to the insertion of a catheter with a cannula that was larger than the patient's artery. Management and Outcome : Fortunately, excessive bleeding due to the size-mismatched cannula was prevented by an unintentional complication of the closing device, which saved the patient's life. She underwent a right common femoral artery thrombectomy and patch angioplasty. Hospital guidelines have changed regarding the surgical removal of ECMO cannulas. Discussion : This report aims to highlight the importance of two aspects that are critical to a successful outcome: individualized cannula selection followed by precise insertion and removal and postoperative evaluation of a patient's final status.

Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant genetic disorder. Although DM1 is primarily characterized by progressive muscular weakness, it exhibits many multisystemic manifestations, such as cognitive deficits, cardiac conduction abnormalities, and cataracts, as well as endocrine and reproductive issues. Additionally, the gastrointestinal (GI) tract is frequently affected, encompassing the entire digestive tract. However, the underlying causes of these GI symptoms remain uncertain, whether it is biomechanical problems of the intestine, involvement of bacterial communities, or both. The primary objective of this study is to investigate the structural changes in the gut microbiome of DM1 patients. To achieve this purpose, 35 patients with DM1 were recruited from the DM-Scope registry of the neuromuscular clinic in the Saguenay-Lac-St-Jean region of the province of Québec, Canada. Stool samples from these 35 patients, including 15 paired samples with family members living with them as controls, were collected. Subsequently, these samples were sequenced by 16S MiSeq and were analyzed with DADA2 to generate taxonomic signatures. Our analysis revealed that the DM1 status correlated with changes in gut bacterial community. Notably, there were differences in the relative abundance of Bacteroidota, Euryarchaeota, Fusobacteriota, and Cyanobacteria Phyla compared to healthy controls. However, no significant shift in gut microbiome community structure was observed between DM1 phenotypes. These findings provide valuable insights into how the gut bacterial community, in conjunction with biomechanical factors, could potentially influence the gastrointestinal tract of DM1 patients., Competing Interests: The authors have declared that no competing interests exist., (© 2024 The Authors.)

Introduction: Myotonic dystrophy type 1 (DM1) is a hereditary neuromuscular disorder affecting the central nervous system (CNS). Although sex differences have been explored in other neuromuscular disorders, research on this topic in DM1 remains limited. The present study aims to analyze sex differences (both the patient's and disease-transmitting parent's sex) with a focus on CNS outcomes., Methods: Retrospective data from 146 non-congenital DM1 patients were analyzed, including clinical, molecular, neuropsychological, and neuroradiological data. Sex and inheritance pattern differences were analyzed using t-tests, and ANOVA analyses were conducted to address the interactions., Results: Overall, no significant sex differences were observed except in certain cognitive domains. However, individuals with maternal inheritance showed larger CTG expansion size, lower estimated IQs, and poorer performance on visual memory, executive functions, and language domains than those with paternal inheritance. Notably, IQ performance was independently influenced by inheritance pattern and CTG expansion., Discussion: This study is the first to delve into sex differences in DM1 with a focus on CNS outcomes. While the results revealed the absence of a sex-specific clinic-molecular profile, more substantial CNS differences were observed between patients with maternal and paternal inheritance patterns. The hypothetical existence of genomic imprinting and its potential mechanism are discussed. These findings hold potential implications for aiding clinical management by improving genetic counseling and predicting disease severity and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Garmendia, Labayru, Aliri, López de Munain and Sistiaga.)

Cognitive deficits and abnormal cognitive aging have been associated with Myotonic dystrophy type 1 (DM1), but the knowledge of the extent and progression of decline is limited. The aim of this study was to examine the prevalence of signs of neurocognitive disorder (mild cognitive impairment and dementia) in adult patients with DM1. A total of 128 patients with childhood, juvenile, adult, and late onset DM1 underwent a screening using the Montreal Cognitive Assessment (MoCA). Demographic and clinical information was collected. The results revealed that signs of neurocognitive disorder were relatively rare among the participants. However, 23.8 % of patients with late onset DM1 (aged over 60 years) scored below MoCA cut-off (=23), and this group also scored significantly worse compared to patients with adult onset. Age at examination were negatively correlated with MoCA scores, although it only explained a small portion of the variation in test results. Other demographic and clinical factors showed no association with MoCA scores. In conclusion, our findings indicate a low prevalence of signs of neurocognitive disorder in adult patients with DM1, suggesting that cognitive deficits rarely progress to severe disorders over time. However, the performance of patients with late onset DM1 suggests that this phenotype warrants further exploration in future studies, including longitudinal and larger sample analyses., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsChristopher Lindberg reports financial support was provided by NEURO Sweden., (© 2024 The Authors.)

Skeletal muscles play key roles in movement, posture, thermogenesis, and whole-body metabolism. Autophagy plays essential roles in the regulation of muscle mass, function and integrity. However, the molecular machinery that regulates autophagy is still incompletely understood. In our recent study, we identified and characterized a novel Forkhead Box O (FoxO)-dependent gene, PHAF1/MYTHO (phagophore assembly factor 1/macro-autophagy and youth optimizer), as a novel autophagy regulator that controls muscle integrity. MYTHO/PHAF1 is upregulated in multiple conditions leading to muscle atrophy, and downregulation of its expression spares muscle atrophy triggered by fasting, denervation, cachexia and sepsis. Overexpression of PHAF1/MYTHO is sufficient to induce muscle atrophy. Prolonged downregulation of PHAF1/MYTHO causes a severe myopathic phenotype, which is characterized by impaired autophagy, muscle weakness, myofiber degeneration, mammalian target of rapamycin complex 1 (mTORC1) hyperactivation and extensive ultrastructural defects, such as accumulation of proteinaceous and membranous structures and tubular aggregates. This myopathic phenotype is attenuated upon administration of the mTORC1 inhibitor rapamycin. These findings position PHAF1/MYTHO as a novel regulator of skeletal muscle autophagy and tissue integrity.

Introduction: Myotonic dystrophy type 1 (DM1) and 2 (DM2) are genetically determined progressive muscular disorders with multisystemic affection, including brain involvement. Transcranial sonography (TCS) is a reliable diagnostic tool for the investigation of deep brain structures. We sought to evaluate TCS findings in genetically confirmed DM1 and DM2 patients, and further correlate these results with patients' clinical features., Methods: This cross-sectional study included 163 patients (102 DM1, 61 DM2). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) as well as the diameter of the third ventricle (DTV) were assessed by TCS. Patients were evaluated using the Hamilton Depression Rating Scale, Fatigue Severity Scale and Daytime Sleepiness Scale., Results: SN hyperechogenicity was observed in 40% of DM1 and 34% of DM2 patients. SN hypoechogenicity was detected in 17% of DM1 and 7% of DM2 patients. BR hypoechogenicity was found in 36% of DM1 and 47% of DM2 subjects. Enlarged DTV was noted in 19% of DM1 and 15% of DM2 patients. Older, weaker, depressive, and fatigued DM1 patients were more likely to have BR hypoechogenicity (p < 0.05). DTV correlated with age and disease duration in DM1 (p < 0.01). In DM2 patients SN hyperechogenicity correlated with fatigue. Excessive daytime sleepiness was associated with hypoechogenic BR (p < 0.05) and enlarged DVT (p < 0.01) in DM2 patients., Conclusions: TCS is an easy applicable and sensitive neuroimaging technique that could offer new information regarding several brainstem structures in DM1 and DM2. This may lead to better understanding of the pathogenesis of the brain involvement in DM with possible clinical implications., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Milija Mijajlovic reports a relationship with Heliyon that includes: board membership., (© 2024 Published by Elsevier Ltd.)

Gastrointestinal and urological symptoms are frequently reported by people with myotonic dystrophy type 1 (DM1) but have remained understudied. In a cross-sectional study, frequency, nature, treatment and impact of gastrointestinal and urological symptoms in children with DM1 aged 5-18 years were assessed. We included 58 children (30 males, 28 females) with a mean age of 13 years; 74.1 % reported at least one gastrointestinal symptom. Abdominal pain was the most frequently reported symptom (51.7 %), followed by dysphagia (41.8 %), diarrhoea (36.2 %), encopresis (36.0 %), constipation (32.7 %), bloating and flatulence (both 25.9 %). The most frequently reported urological symptoms were difficulty with toilet training (59.3 %), urinary incontinence (22.0 %), enuresis nocturna (10.3 %) and voiding (23.5 % hesitancy, 4.8 % intermittency and 13.8 % dysuria). The majority considered urological and gastrointestinal symptoms to have a negative influence on their daily life; 22.4 % of parents reported severe influence on daily family life (shame, social restrictions, school absence and concerns for their children's future). Considering the high prevalence of urological and gastrointestinal symptoms in children with DM1 and their influence on daily life it is key to correctly recognize, diagnose and treat these symptoms. We recommend screening for gastrointestinal and urological symptoms in the standard of care for children with DM1., Competing Interests: Declaration of competing interest None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Despite the increased prevalence of comorbid attention deficit hyperactivity disorder (ADHD) in children with myotonic dystrophy type 1, the effects of methylphenidate treatment on associated cognitive deficits in this population is not yet investigated., Case: We describe a case study of an eleven-year-old male patient with myotonic dystrophy type 1 and comorbid ADHD that was treated with methylphenidate in a twice daily regime (0.60 mg/kg/day). Positive effects on learning and cognition were reported by the parents and teachers. No negative side effects were reported. Sequential neuropsychological assessments before and 45 minutes after methylphenidate intake were conducted to quantify the cognitive effects of methylphenidate treatment. Significant improvements in regulation of attention were behaviorally observed and were quantified using eye tracking technology., Conclusion: We conclude that methylphenidate may be an effective treatment for ADHD-related cognitive deficits and learning difficulties in children with myotonic dystrophy type 1 which merits further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is one of the monogenic neurological diseases that neurologists most often experience. DM1 can develop several symptoms, including muscle weakness, gait disturbance, urinary incontinence, and cognitive decline. Other hand, normal pressure hydrocephalus (NPH) is more frequent in the elderly population and is characterized by a triad of symptoms, gait disturbance, urinary urge incontinence, and cognitive decline. Therefore, some symptoms overlap between DM1 and NPH. In this report, we described a case of DM1 that presented with a triad of NPH, and NPH-like changes in brain images. A 54-year-old man with DM1 visited our hospital for rehabilitation. He had a history of dyslipidemia, diabetes, and cataracts. He developed muscle weakness, blepharoptosis, and dysarthria at 43 years. Neuro-exam revealed percussion and grip myotonia, distal muscle weakness and atrophy, broad-based gait, and urinary incontinence. The mini-mental state examination score was 18. Brain magnetic resonance imaging revealed enlarged lateral and third ventricles and Evans index was 0.38 (NPH criterion; >0.3), which was mimicking for NPH. Tap test (TT) was evaluated twice. First TT improved clinical symptoms slightly, but second was unremarkable. Based on the second TT result, we could not diagnose with NPH and could prevent unnecessary surgical shunting. Brain imaging of DM1 can show an NPH-like appearance in patients older than 50. Although TT is the gold standard for diagnosing NPH, its sensitivity and specificity vary among reports. TT results should be interpreted with caution before performing a surgical shunt. If necessary, multiple TTs should be considered in DM1 patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Suzuki et al.)

Study Objectives: This study explores polysomnographic and multiple sleep latency test (MSLT) differences between myotonic dystrophy type 1/type 2 (DM1/DM2) patients and controls., Methods: An electronic literature search was conducted in MEDLINE, EMBASE, All EBM databases, and Web of Science from inception to Aug 2023., Results: Meta-analyses revealed significant reductions in sleep efficiency, N2 percentage, mean SpO2, and MSLT measured mean sleep latency, and increases in N3 sleep, wake time after sleep onset, apnea hypopnea index, and periodic limb movement index in DM1 patients compared with controls. However, any differences of polysomnographic sleep change between DM2 patients and controls could not be established due to limited available studies., Conclusions: Multiple significant polysomnographic abnormalities are present in DM1. More case-control studies evaluating polysomnographic changes in DM2 compared with controls are needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by the expansion of a noncoding triplet repeat., Methods: A cross-sectional study was performed to characterize pediatric patients with DM1 followed in a tertiary hospital over the last 29 years, comparing the congenital and the childhood/juvenile-onset forms., Results: Thirty-seven patients (59.5 % male) were included, with a median age at the latest assessment of 16.8 years and a median follow-up of 7.7 years. Eleven patients were lost to follow-up, and two died. Twenty-five had congenital DM1 (CDM1), and this form had significantly higher triplet repeat length, history of polyhydramnios, lower median age at diagnosis, and first and last assessment. Common symptoms included distal skeletal muscle weakness (75.7 %) and facial involvement (94.6 %), along with dysphonia/dysarthria (73.0 %) and myotonia (73.0 %). Delayed independent ambulation frequency was significantly higher for CDM1 cases. Skeletal deformities affected 54.1 %, with talipes equinovarus and scoliosis occurring exclusively in CDM1 patients. Cognitive deficit was present in 75.7 % of cases. Polysomnograms revealed seven cases of obstructive sleep apnea and two of hypoventilation. Noninvasive ventilation was used in nine cases, and three had recurrent respiratory infections. The cardiovascular system was affected in 21.6 % of cases. Gastrointestinal issues included constipation (24.3 %), feeding difficulties (16.2 %), and cholelithiasis (5.4 %). Cataracts, epilepsy, and diabetes mellitus were reported in two cases each., Conclusion: Our study highlights the diverse spectrum of severity and multiorgan involvement of DM1 in pediatric patients. It underscores the importance of establishing a pediatric-specific standard of care to enhance health outcomes through comprehensive multidisciplinary management., Competing Interests: Declaration of competing interest The authors declare no conflict of interest relevant to this study., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Background: Myotonic dystrophy type 1 (DM1) is a slowly progressive disease caused by abnormal CTG repetitions on the dystrophia myotonica protein kinase (DMPK) gene. Long mRNA from CTG repetitions stabilizes in nuclear foci and sequester muscleblind-like splicing regulator 1 (MBNL1). Cardinal signs of DM1 include muscle wasting and weakness. The impacts of DM1 progression on skeletal muscle are under-researched., Objective: Identifying physiopathological markers related to maximal strength loss over time in DM1., Methods: Twenty-two individuals with DM1 participated in two maximal isometric muscle strength (MIMS) evaluations of their knee extensors and two vastus lateralis muscle biopsies, 3 years apart. Muscle fiber typing, size (including minimal Feret's diameter [MFD] and atrophy/hypertrophy factors [AF/HF]), and nuclear foci and MBNL1 colocalization (foci/MBNL1+) were evaluated. Immunoblotting was used to measure glycogen synthase kinase-3 beta (GSK3β), p62, LC3BI, LC3BII, and oxidative phosphorylation proteins., Results: There are significant correlations between the fold changes of MIMS with type 1 fiber MFD (ρ= 0.483) and AF (ρ= -0.514). Regression analysis shows that baseline percentage of foci/MBNL1+ nuclei and strength training explain 44.1% of foci/MBNL1+ nuclei percentage variation over time. There are fair to excellent correlations between the fold changes of MIMS and GSK3β (ρ= 0.327), p62 (ρ= 0.473), LC3BI (ρ= 0.518), LC3BII (ρ= -0.391) and LC3BII/LC3BI (ρ= -0.773)., Conclusion: Type 1 MFD decrease and AF increase are correlated with MIMS loss. There seems to be a plateau effect in foci/MBNL1+ nuclei accumulation and strength training helps decrease this accumulation. Autophagy marker LC3BII/LC3BI ratio has a good biomarker potential of MIMS loss, but more investigations are needed.

Objectives: The mechanism and pathological substrate of arrhythmogenic events in dystrophic myopathy type 1 (DM1) have not been fully established, especially for patients without progression of motor and/or cardiac disability. Therefore, we aimed to clarify the pathological appearance and genetic factors, other than CTG repeats in DMPK, associated with sudden cardiac death in patients with DM1., Methods: A pathological investigation including the cardiac conduction system in the heart and whole-exome sequencing was conducted for three young adults (Patient 1; 25-year-old female, Patient 2; 35-year-old female, Patient 3; 18-year-old male) with DM1 who suffered sudden death., Results: Only Patient 1 showed abnormal electrocardiogram findings before death. The pathological investigation showed severe fibrosis of the atrioventricular conduction system in Patient 1 and severe fatty infiltration in the right ventricle in Patient 2. Several minimal necrotic/inflammatory foci were found in both patients. Patient 3 showed no significant pathological findings. A genetic investigation showed CORIN&#95;p.W813* and MYH2&#95;p. R793* in Patient 1, KCNH2&#95;p. V794D and PLEC&#95;p. A4147T in Patient 2, and SCN5A&#95;p.E428K and SCN3B&#95; p.V145L in Patient 3 as highly possible pathogenic variants., Conclusion and Relevance: The present study showed varied heart morphology in young adults with DM1 and sudden death. Synergistic effects of various genetic factors other than CTG repeats may increase the risk of sudden cardiac death in DM1 patients, even if signs of cardiac and skeletal muscle involvement are mild. Comprehensive genetic investigations, other than CTG repeat assessment, may be useful to estimate the risk of sudden cardiac death in DM1 patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Myotonic dystrophy type 1 (DM1) is an autosomal dominant trinucleotide disorder that often leads to respiratory dysfunction resulting in hypoventilation symptoms, reduced quality of life and causing premature death if untreated. To early identify symptoms of hypoventilation, the Respicheck questionnaire was developed as a screening tool. Symptomatic therapies like inspiratory muscle training (IMT) are recommended to strengthen respiratory muscles and reduce or even prevent hypoventilation symptoms. Our study aimed to evaluate the Respicheck questionnaire's suitablility to monitor the efficacy of IMT. Patients with genetically confirmed DM1 were randomly assigned to either IMT - endurance or strength training, or control group. At baseline, end of study and four interim visits, pulmonary function tests, Respicheck questionnaire and Epworth sleepiness scale were assessed. While patients in training groups achieved a substantial improvement after nine months of regular IMT in pulmonary function tests, the Respicheck score did not improve likewise. Similarly, the ESS score did not change significantly in both training and control groups. Consequently, we conclude that either improvement of respiratory function is not necessarily associated with clinical improvement, or respiratory muscle weakness was not the only reason for hypoventilation syndrome, or both questionnaires are not sensitive enough to detect slight clinical changes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kristina Gutschmidt reports financial support was provided by Deutsche Gesellschaft für Muskelkranke e.V. Stephan Wenninger reports financial support was provided by Deutsche Gesellschaft für Muskelkranke e.V., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Myotonic dystrophy type 1 (DM1) is a neuromuscular multisystem disease. Early involvement of facial muscles may produce an extra load on the temporomandibular joint (TMJ) in DM1., Objectives: This study aimed to investigate the morphological analyses of the bone components of temporomandibular joint (TMJ), and dentofacial morphology in myotonic dystrophy type 1 (DM1) patients by cone-beam computed tomography (CBCT)., Methods: Sixty-six individuals (33 DM1, and 33 healthy subjects) age ranging from 20 to 69 were included in the study. Clinical examinations of the patients' TMJ regions and evaluation of dentofacial morphology (maxillary deficiency, open-bite, deep palate and cross-bite) were performed. Dental occlusion was determined based on Angle's classification. CBCT images were evaluated regarding mandibular condyle morphology (convex, angled, flat and round) and osseous changes observed in the condyle (normal, osteophyte, erosion, flattening, sclerosis). DM1-specific morphological and bony TMJ alterations were determined., Results: DM1 patients showed a high prevalence of morphological and osseous TMJ changes, and statistically significant skeletal alterations. The analysis of CBCT scans indicated the prevalent condylar shape among patients with DM1 was flat, the main osseous abnormality was flattening, there was a tendency towards skeletal Class II and a posterior cross-bite was frequently detected in DM1 patients. There was no statistically significant difference between the genders on the parameters evaluated in both groups., Conclusion: Adult patients with DM1 presented a high frequency of crossbite, tendency to skeletal Class II and morphological osseous alterations of TMJ. The analysis of the morphological condylar alterations in patients with DM1 may be beneficial in the diagnosis of TMJ disorders. This study reveals DM1-specific morphological and osseous TMJ alterations to provide an appropriate orthodontic/orthognathic treatment planning to patients., (© 2023 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (I Na ), L-type calcium current (I CaL ), transient outward potassium current (I to ), and APs were recorded using the patch-clamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for I to and I CaL with a positive shift in steady state activation of L-type calcium channels carrying I CaL in DMSXL homozygous mice compared with WT mice. I Na densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of I to , and I CaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2023 Ginjupalli, Cupelli, Reisqs, Sleiman, El-Sherif, Gourdon, Puymirat, Chahine and Boutjdir.)

Myotonic dystrophy type 1 (DM1) is a genetic disorder that causes muscle weakness and myotonia. In DM1 patients, cardiac electrical manifestations include conduction defects and atrial fibrillation. DM1 results in the expansion of a CTG transcribed into CUG-containing transcripts that accumulate in the nucleus as RNA foci and alter the activity of several splicing regulators. The underlying pathological mechanism involves two key RNA-binding proteins (MBNL and CELF) with expanded CUG repeats that sequester MBNL and alter the activity of CELF resulting in spliceopathy and abnormal electrical activity. In the present study, we identified two DM1 patients with heart conduction abnormalities and characterized their hiPSC lines. Two differentiation protocols were used to investigate both the ventricular and the atrial electrophysiological aspects of DM1 and unveil the impact of the mutation on voltage-gated ion channels, electrical activity, and calcium homeostasis in DM1 cardiomyocytes derived from hiPSCs. Our analysis revealed the presence of molecular hallmarks of DM1, including the accumulation of RNA foci and sequestration of MBNL1 in DM1 hiPSC-CMs. We also observed mis-splicing of SCN5A and haploinsufficiency of DMPK. Furthermore, we conducted separate characterizations of atrial and ventricular electrical activity, conduction properties, and calcium homeostasis. Both DM1 cell lines exhibited reduced density of sodium and calcium currents, prolonged action potential duration, slower conduction velocity, and impaired calcium transient propagation in both ventricular and atrial cardiomyocytes. Notably, arrhythmogenic events were recorded, including both ventricular and atrial arrhythmias were observed in the two DM1 cell lines. These findings enhance our comprehension of the molecular mechanisms underlying DM1 and provide valuable insights into the pathophysiology of ventricular and atrial involvement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Pierre, Djemai, Chapotte-Baldacci, Pouliot, Puymirat, Boutjdir and Chahine.)

Objective  to report a myotonic dystrophy type 1 (MD1) subject with obstructive sleep apnea syndrome treated with oral appliance. Methods  A review of individual's history and records, associated with a photographic register of all diagnostic methods and literature research about the topic were done. Final Statements  This case depicts the therapeutical choices disposable to treat subjects with obstructive sleep apnea and DM1. Although considered an uncommon treatment, the oral appliances, if well indicated in adequately selected cases, can satisfactorily improve respiratory parameters, symptoms and quality of life., Competing Interests: Conflict of Interests The authors have no conflict of interests to declare., (Brazilian Sleep Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Repeat expansion diseases are a group of neuromuscular and neurodegenerative disorders characterized by expansions of several successive repeated DNA sequences. Currently, more than 50 repeat expansion diseases have been described. These disorders involve diverse pathogenic mechanisms, including loss-of-function mechanisms, toxicity associated with repeat RNA, or repeat-associated non-ATG (RAN) products, resulting in impairments of cellular processes and damaged organelles. Mitochondria, double membrane organelles, play a crucial role in cell energy production, metabolic processes, calcium regulation, redox balance, and apoptosis regulation. Its dysfunction has been implicated in the pathogenesis of repeat expansion diseases. In this review, we provide an overview of the signaling pathways or proteins involved in mitochondrial functioning described in these disorders. The focus of this review will be on the analysis of published data related to three representative repeat expansion diseases: Huntington's disease, C9orf72 -frontotemporal dementia/amyotrophic lateral sclerosis, and myotonic dystrophy type 1. We will discuss the common effects observed in all three repeat expansion disorders and their differences. Additionally, we will address the current gaps in knowledge and propose possible new lines of research. Importantly, this group of disorders exhibit alterations in mitochondrial dynamics and biogenesis, with specific proteins involved in these processes having been identified. Understanding the underlying mechanisms of mitochondrial alterations in these disorders can potentially lead to the development of neuroprotective strategies.

Introduction/aims: Urinary titin, an easy-to-obtain marker, has been investigated in muscular dystrophies, but not in myotonic dystrophy type 1 (DM1). We investigated the role of titin as a biomarker of muscle injury in DM1., Methods: We compared the urinary titin N-fragment/creatinine ratio in 29 patients with DM1 vs. 30 healthy controls. We also recorded clinical data such as muscle strength, serum creatine kinase, DM1-related outcome measures, and the 20-item DM1-activ questionnaire. The severity of the disease was graded using the Muscular Impairment Rating Scale (MIRS)., Results: The titin/creatinine ratio was significantly higher in the urine samples of DM1 patients than of healthy controls (median ± mean absolute deviation [MAD]: 39.313 ± 26.546 vs. 6.768 ± 5.245 pmol/mg creatinine; P < .001), and was related to muscle impairment graded by MIRS (τ = 0.503, P = .038)., Discussion: Urinary titin may be a biomarker for DM1. Long-term follow-up of DM1 patients is needed to investigate the potential role of titin as a biomarker for disease activity and progression., (© 2023 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Secondary structures formed by expanded CUG RNA are involved in the pathobiology of myotonic dystrophy type 1. Understanding the molecular basis of toxic RNA structures can provide insights into the mechanism of disease pathogenesis and accelerate the drug discovery process. Here, we report the crystal structure of CUG repeat RNA containing three U-U mismatches between C-G and G-C base pairs. The CUG RNA crystallizes as an A-form duplex, with the first and third U-U mismatches adopting a water-mediated asymmetric mirror isoform geometry. We found for the first time that a symmetric, water-bridged U-H 2 O-U mismatch is well tolerated within the CUG RNA duplex, which was previously suspected but not observed. The new water-bridged U-U mismatch resulted in high base-pair opening and single-sided cross-strand stacking interactions, which in turn dominate the CUG RNA structure. Furthermore, we performed molecular dynamics simulations that complemented the structural findings and proposed that the first and third U-U mismatches are interchangeable conformations, while the central water-bridged U-U mismatch represents an intermediate state that modulates the RNA duplex conformation. Collectively, the new structural features provided in this work are important for understanding the recognition of U-U mismatches in CUG repeats by external ligands such as proteins or small molecules., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Myotonic dystrophy type 1 (DM1) is the most prevalent muscular dystrophy in adults. People with DM1 might represent a high-risk population for respiratory infections, including COVID-19. Our aim was to evaluate the characteristics of COVID-19 infection and vaccination rate in DM1 patients., Methods: This cross-sectional cohort study included 89 patients from the Serbian registry for myotonic dystrophies. Mean age at testing was 48.4 ± 10.4 years with 41 (46.1%) male patients. Mean duration of the disease was 24.0 ± 10.3 years., Results: COVID-19 infection was reported by 36 (40.4%) DM1 patients. Around 14% of patients had a more severe form of COVID-19 requiring hospitalization. The severity of COVID-19 was in accordance with the duration of DM1. A severe form of COVID-19 was reported in 20.8% of patients who were not vaccinated against SARS-CoV-2 and in none of the vaccinated ones. The majority of 89 tested patients (66.3%) were vaccinated against SARS-CoV-2. About half of them (54.2%) received three doses and 35.6% two doses of vaccine. Mild adverse events after vaccination were recorded in 20.3% of patients., Conclusions: The percentage of DM1 patients who suffered from COVID-19 was like in general population, but with more severe forms in DM1, especially in patients with longer DM1 duration. The study indicated an overall favorable safety profile of COVID-19 vaccines among individuals with DM1 and its ability to protect them from severe COVID-19., (© 2023. The Author(s).)

Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Chronic hypoventilation due to involvement of respiratory muscles is a frequent symptom in autosomal dominant inherited myotonic dystrophies, especially in type 1 (DM1), leading to a severely reduced quality of life, an early need for ventilatory support, or premature death. Thus, early knowledge of respiratory muscle weakness is essential to initiate further diagnostic and therapeutic measures. To get early, simple, and reliable information about respiratory impairment in DM patients, we performed a prospective controlled cohort study with DM1 and DM2 patients analysing the suitability of 'Respiratory involvement symptom checklist (Respicheck) as a clinically meaningful screening questionnaire for ventilatory impairment in patients with DM1 or DM2. Clinical assessments included a one-time pulmonary function test (spirometry and manometry) and the completion of the Respicheck. 172 participants were enrolled in this study (74 DM1, 72 DM2, 26 healthy controls). With a cut-off Respicheck CAT score of 4, the Respicheck can distinguish between patients with and without respiratory impairment with higher sensitivity and positive predictive value for DM1 than DM2 patients (DM1: sensitivity 77-87; positive predictive value 50-94%; DM2: sensitivity 67-80%; positive predictive value 14-38). In summary, our results confirm a clinically meaningful use of the Respicheck to detect respiratory impairments predominantly in DM1 patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cognitive and behavioural problems may be predominant in the clinical picture of myotonic dystrophy (DM1) in childhood. This can lead to a diagnostic delay and thus prevent optimal therapeutic measures., Objective: To obtain an overview of children with DM1 in our health region and study their cognitive and behavioural function, quality of life and neurological status., Methods: Patients diagnosed with DM1 were recruited to this cross-sectional study through local habilitation teams of our health region. Neuropsychological testing and physical examination were performed for the majority. For some patients information was retrieved from medical records and through telephone interviews. A questionnaire was administered regarding quality of life., Results: 27 subjects <18 years diagnosed with DM1 were identified, giving a frequency of DM1 of 4.3/100 000 in this age group. Twenty consented to participate. Five had congenital DM1. Most of the participants had only mild neurological deficits. Two with congenital type had hydrocephalus requiring a shunt. Ten, whereof none with congenital DM1, had a cognitive function within normal range. Three were diagnosed with an autism spectrum disorder, and additional three were reported with autistic traits. Many parents reported social and school problems for their child., Conclusions: Intellectual disability and varying degrees of autistic behaviour were quite common. Motor deficits were most often mild. A strong focus regarding support at school and in social communication is needed for children growing up with DM1., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Myotonic dystrophy type 1 (DM1, OMIM 160900) is a rare autosomal dominant hereditary disease. A case of DM1 patient with early onset diabetes and decreased muscle strength was treated in the Department of Endocrinology, Third Xiangya Hospital, Central South University. The peripheral blood of the patient was collected to extract DNA for gene detection. It was found that the triple nucleotide CTG repeat in the 3'-untranslated region (3'-UTR) of the dystrophia myotonica protein kinase ( DMPK ) gene was more than 100 times, and the diagnosis of DM1 was clear. For diabetes patients with multiple system abnormalities such as muscle symptoms, attention should be paid to the screening of DM1, a rare disease.

Myotonic dystrophy type 1 (DM1) is a neuromuscular disease that originates from an expansion of CTG microsatellites in the 3' untranslated region of the DMPK gene, thus leading to the expression of transcripts containing expanded CUG repeats ( CUGexp ). The pathophysiology is explained by a toxic RNA gain of function where CUGexp RNAs form nuclear aggregates that sequester and alter the function of MBNL splicing factors, triggering splicing misregulation linked to the DM1 symptoms. There is currently no cure for DM1, and most therapeutic strategies aim at eliminating CUGexp-DMPK transcripts. Here, we investigate a DMPK -promoter silencing strategy using CRISPR interference as a new alternative approach. Different sgRNAs targeting the DMPK promoter are evaluated in DM1 patient muscle cells. The most effective guides allowed us to reduce the level of DMPK transcripts and CUGexp -RNA aggregates up to 80%. The CUGexp-DMPK repression corrects the overall transcriptome, including spliceopathy, and reverses a physiological parameter in DM1 muscle cells. Its action is specific and restricted to the DMPK gene, as confirmed by genome-wide expression analysis. Altogether, our findings highlight DMPK -promoter silencing by CRISPRi as a promising therapeutic approach for DM1., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by the involvement of exocrine glands with dryness of mouth and eyes as typical clinical manifestations, and may also have extra-glandular organ involvement. Myotonic dystrophy type 1 (DM1) is the most common type of adult-onset muscular dystrophy, which can lead to progressive muscle weakness and myotonia. The coexistence of pSS with DM1 was rarely reported. We here report a Chinese female pSS patient with progressive type II respiratory failure as a major manifestation and finally diagnosed with DM1 by genetic testing., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Antisense oligonucleotide (ASO) therapies for myotonic dystrophy type 1 (DM1) are based on elimination of transcripts containing an expanded repeat or inhibition of sequestration of RNA-binding proteins. This activity is achievable by both degradation of expanded transcripts and steric hindrance, although it is unknown which approach is superior. We compared blocking ASOs with RNase H-recruiting gapmers of equivalent chemistries. Two DMPK target sequences were selected: the triplet repeat and a unique sequence upstream thereof. We assessed ASO effects on transcript levels, ribonucleoprotein foci and disease-associated missplicing, and performed RNA sequencing to investigate on- and off-target effects. Both gapmers and the repeat blocker led to significant DMPK knockdown and a reduction in (CUG) exp foci. However, the repeat blocker was more effective in MBNL1 protein displacement and had superior efficiency in splicing correction at the tested dose of 100 nM. By comparison, on a transcriptome level, the blocking ASO had the fewest off-target effects. In particular, the off-target profile of the repeat gapmer asks for cautious consideration in further therapeutic development. Altogether, our study demonstrates the importance of evaluating both on-target and downstream effects of ASOs in a DM1 context, and provides guiding principles for safe and effective targeting of toxic transcripts., Competing Interests: D.G.W. is inventor on patents related to ASOs for treatment of myotonic dystrophy type 1., (© 2023 The Author(s).)

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by the excessive expansion of noncoding CTG repeats, which when transcribed affects the functions of RNA-binding factors with adverse effects on alternative splicing, processing, and stability of a large set of muscular and cardiac transcripts. Among these effects, inefficient processing and down-regulation of muscle- and heart-specific miRNA, miR-1, have been reported in DM1 patients, but the impact of reduced miR-1 on DM1 pathogenesis has been unknown. Here, we use Drosophila DM1 models to explore the role of miR-1 in cardiac dysfunction in DM1. We show that miR-1 down-regulation in the heart leads to dilated cardiomyopathy (DCM), a DM1-associated phenotype. We combined in silico screening for miR-1 targets with transcriptional profiling of DM1 cardiac cells to identify miR-1 target genes with potential roles in DCM. We identify Multiplexin (Mp) as a new cardiac miR-1 target involved in DM1. Mp encodes a collagen protein involved in cardiac tube formation in Drosophila. Mp and its human ortholog Col15A1 are both highly enriched in cardiac cells of DCM-developing DM1 flies and in heart samples from DM1 patients with DCM, respectively. When overexpressed in the heart, Mp induces DCM, whereas its attenuation rescues the DCM phenotype of aged DM1 flies. Reduced levels of miR-1 and consecutive up-regulation of its target Mp/Col15A1 might be critical in DM1-associated DCM., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction: Weakness of trunk muscles, fatigue and reduced mobility are features of myotonic dystrophy type 1 (DM1) and may also characterize patients with extrapyramidal disorders.Dysphagia is common in DM1 and parkinsonism and can be predominant compared to other symptom, often requiring surgical tratment., Methods: We describe two cases of patients with DM1 and parkinsonism who arrived at our Center for worsening dysphagia and who showed very similar and peculiar clinical features., Case Reports: The first patient presented initially at the outpatient clinic reporting a 7 year history of progressive difficulties in swallowing and movement slowness. Neurologic examination showed a general bradykinesia, plastic rigidity of upper limbs, diffuse hypotrophy and deep tendon reflexes weakness. MRI scan of brain and spine was unremarkable, but neurophysiological evaluation revealed diffuse myotonic discharges on distal limb muscles. Genetic testing confirmed DM1 diagnosis (CTG range E1).The second patient, presented with an initial diagnosis of parkinsonism due to a 10 years history of gait impairment, generalized weakness and dysphagia. Due to low back pain a neurophysiological study was performed after 5 years from diagnosis of parkinsonism detecting diffuse myotonic discharges and genetic testing confirmed diagnosis of DM1 (CTG range E2).Percutaneous endoscopic gastrostomy (PEG) was severe and burdensome for both patients.To date, only one case of molecularly confirmed DM1 along with parkinsonism has been described. We have described two cases of DM1 and parkinsonism in which swallowing function has been affected by a synergic effect triggered by both muscle condition and extrapyramidal disease., Competing Interests: The authors declare no conflict of interest., (©2023 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Pain is an underestimated finding in myotonic dystrophy type 1 (DM1). We provide a characterization of pain in terms of functional implications through a multidimensional assessment in patients with DM1, focusing on gender differences. We assessed pain through the Brief Pain Inventory (BPI) and its indexes (the Severity Index (SI) and the Interference Index (II)), balance/gait (the Tinetti Performance-Oriented Mobility Assessment (POMA)), functional abilities (the Functional Independence Measure (FIM)), and fatigue (the Fatigue Severity Scale (FSS)). We divided our sample into a mild (<4) and a moderate-severe group (≥4) based on BPI indexes. A between-group analysis was performed. We recruited 23 males and 22 females with DM1. A statistically significant difference was found for the FSS and the BPI-SI ≥ 4, and for all outcomes in the BPI-II ≥ 4 ( p ≤ 0.003). In the female group, all outcomes except for the FIM were statistically significantly worse ( p ≤ 0.004). Dividing our sample into four groups based on gender and the BPI, a statistically significant difference was found for FSS between the two groups with BPI-II ≥ 4 (with worsen score in the female one) ( p < 0.002). Pain in DM1 patients is highly reported and gender related, with increased fatigue and poor balance/gait in the female group.

Objectives: Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, is a chronic, progressive and disabling multisystemic disorder with a broad spectrum of severity that arises from an autosomal-dominant expansion of the Cytosine-Thymine-Guanine (CTG) triplet repeat in the 3' untranslated region of the DMPK gene (19q13.3)., Case Presentation: In this study, we report the case of a family with several intergenerational expansions of the CTG repeat, with an additional case of a false suspicion of contraction phenomenon due to TP-PCR limitations., Conclusions: The meiotic instability of the (CTG) n repeats leads to genetic anticipation where increased size of DM1 mutation and a more severe phenotype have been reported in affected individuals across generations. Even if extremely rare, a decrease in the CTG repeat size during transmission from parents to child can also occur, most frequently during paternal transmissions., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease in children causing sleep and respiratory disorders that are poorly described in the literature compared to adult forms. This retrospective observational study was performed at the Armand Trousseau University Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France. We retrospectively collected data from lung function tests, nocturnal gas exchange recordings, and polysomnography of 24 children with DM1. 39% of the children with DM1 reported respiratory symptoms indicative of sleep disordered breathing. Three patients (12%) presented with a restrictive respiratory pattern, 10 (42%) with a sleep apnoea syndrome, mainly of obstructive origin (2/10 with severe obstructive sleep apnea syndrome), and 11 (45%) with nocturnal alveolar hypoventilation. Non-invasive ventilation (NIV) was indicated in 9 (37.5%) children, although tolerance was poor. No significant deterioration in respiratory function or nocturnal gas exchange was observed during the NIV-free period. This study provides new and useful insights into DM1 disease evolution in children to better adapt for respiratory follow-up and management. This highlights the need for future research to better understand the origin of respiratory and sleep disorders in patients with DM1., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest related to this article to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. Cardiac involvement is reported in 80% of cases and includes conduction disturbances, arrhythmias, subclinical diastolic and systolic dysfunction in the early stage of the disease; in contrast, severe ventricular systolic dysfunction occurs in the late stage of the disease. Echocardiography is recommended at the time of diagnosis with periodic revaluation in DM1 patients, regardless of the presence or absence of symptoms. Data regarding the echocardiographic findings in DM1 patients are few and conflicting. This narrative review aimed to describe the echocardiographic features of DM1 patients and their prognostic role as predictors of cardiac arrhythmias and sudden death.