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Background: Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder that classically presents with symptoms associated with myotonia, early onset cataracts, and muscular weakness, although the presentation and pattern of disease progression is quite varied. Presenting symptoms are well documented among adults with DM1. However, less is known about the co-occurrence of symptoms over time. We aimed to use factor analysis to explore the correlation pattern of signs and symptoms (S/S) that emerged during the clinical course. Results: Clinical records of 228 individuals with adult onset DM1 were abstracted using the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from a six-site cohort in the United States during an eight-year study period. Factor analysis was used to group the correlated S/S into latent factors. Three factors were identified. Group 1: 'Facial Weakness/Myotonia' includes the two most common S/S, as indicated by its name. Group 2: 'Skeletal Muscle Weakness' includes eight muscular S/S and is more frequently reported by males and those with older age at onset. Group 3: 'Gastrointestinal distress/Sleepiness' includes four non-muscular S/S and hand stiffness. The abstracted medical records reported that over 63% of individuals had S/S from all three groups. Associations of covariates with factor scores were also examined using linear regression. CTG repeat length was significantly positively associated with higher factor scores for all three factors. Conclusions: This study identified three latent factors of S/S which accumulated during the clinical course of adult onset DM1. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Type 1 myotonic dystrophy (DM1) is a neuromuscular disorder of multiple organ systems with important electrophysiologic (EP) manifestations, leading to a cumulative incidence of sudden death of 6.6%. Due to genetic anticipation, there is a pediatric subset of this patient population. However, most EP research on DM1 patients has been in adults, making cardiac care for pediatric patients difficult and directed by adult guidelines which often leads to cardiovascular implantable electronic device (CIED) implants. We sought to investigate the prevalence of CIEDs in the pediatric DM1 population. Methods: The Vizient® Clinical Data Base was queried from October 2019 to October 2023 for admissions with and without ICD‐10 code for myotonic dystrophy (G71.11), with and without codes for presence of a pacemaker or ICD (Z95.0, Z95.810). Patients who were identified were stratified by age: Pediatric (0–21 years) and Adult (22–50 years). Results: Prevalence of CIED in pediatric DM1 was 2.1% and in adult DM1 was 15.8%. When comparing to pediatric and adult patients with CIED and without DM1, the odds ratio for CIED in pediatric DM1 was 48.8, compared to 23.3 for CIED in adult DM1. Discussion: There are pediatric DM1 patients who have received CIED despite a lack of data to inform this decision‐making. Further research will be important to ensure appropriate use of CIED in this population and to develop appropriate guidelines to direct management. [ABSTRACT FROM AUTHOR]

Background: Myotonic Dystrophy type 1 (DM1) is an autosomal dominant disease with anticipation due to increased number of CTG repeats in the DMPK gene. Methods: This retrospective, cohort study in Iceland assessed prevalence of DM1, molecular pathology, and patient ascertainment. Data was collected from all major hospitals in Iceland, Medical Director of Health, and independent clinics. Cohort criteria were diagnosis of DM1 on January 1, 2021, or time of death. Population‐based Icelandic Genealogy Database of the Genetical Committee at the University of Iceland was used for genealogy. Results: In Iceland, 221 individuals, including 19 obligate carriers, had been diagnosed with DM1 of which 144 were alive giving a point prevalence of 39 per 100,000 (four times the world average of 9.3). Genealogy analysis identified 45 first‐degree families. Age‐adjusted prevalence ranged between 11 and 66 per 100,000. Average potential years of life lost were 20.5 per person. Where information was available, 63% of ascertainment was based on family history in cascade testing. Conclusion: The differences in age‐adjusted prevalence suggest that the overall point prevalence is an underestimation due to underdiagnosis in younger age groups and lethality in oldest age group. Our data supports use of cascade testing to improve DM1 ascertainment. [ABSTRACT FROM AUTHOR]

Objectives: We characterized blood glucose fluctuations in patients with myotonic dystrophy type 1 (DM1). After confirming the incretin secretion capacity of patients with DM1, we intended to clarify whether dipeptidyl peptidase 4 (DPP-4) inhibitor administration was appropriate in cases of DM1 with diabetes mellitus. Methods: A 48 h continuous glucose monitoring (CGM) was performed in 29 Japanese patients with DM1. An oral glucose tolerance test (OGTT) was performed in patients with DM1 and five disease controls, and levels of blood glucose, insulin, and incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) were measured. DPP-4 inhibitors were administered to patients with diabetes mellitus complicated by DM1, and the CGM results were compared. Results: The CGM showed distinct patterns of blood glucose variability among patients classified by an OGTT pattern with significant differences in glucose parameters such as time above 140 mg/dL and mean amplitude of glycemic excursions between the groups. High sensor glucose values were observed in a certain number of patients who were classified as having normal or impaired glucose tolerance by the OGTT. The CGM confirmed the presence of low glucose levels in several patients. Incretin secretion, the target of DPP-4 inhibitors, was preserved in patients with DM1. DPP-4 inhibitor treatment resulted in lower glucose levels and improved insulin secretion in some patients. Conclusions: This is the first CGM study for DM1 patients. The CGM identified potential early abnormalities in glucose metabolism in DM1. In the future, it will be crucial to explore effective methods for harnessing CGM and assessing it quantitatively in DM1. [ABSTRACT FROM AUTHOR]

Background and purpose: Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder characterized by myotonia and progressive muscle weakness. Beyond the primary symptoms, there is growing concern regarding a higher incidence of certain comorbidities in DM1 patients, including cancer, diabetes, thyroid dysfunction, and cataracts. This study was designed to examine the occurrence of these conditions among patients diagnosed with DM1 in South Korea, using data from the National Health Insurance Service database. Methods: The study undertook a comprehensive review of 3,842 patients diagnosed with DM1 between 2012 and 2018. We assessed the incidence of cancer and the prevalence of diabetes, thyroid dysfunction, and cataracts among these patients, comparing their rates to those in the general population. Results: In the study cohort, 463 out of 3,842 DM1 patients (12.04%) were diagnosed with cancer, indicating a substantial elevation in cancer risk with an overall standard incidence ratio of 1.9 (95% CI = 1.6–2.3, p < 0.01) when compared to the expected rates in the general population. Moreover, the prevalence of diabetes (15.2%) and thyroid dysfunction (17.6%) was noteworthy in the DM1 population. The mean age at which DM1 patients underwent cataract surgery was 55.07 years, noticeably younger than the mean age of 69.25 years for cataract surgery in the general population. Conclusions: DM1 patients have a noteworthy occurrence of several comorbidities such as cancer, diabetes, thyroid dysfunction, and earlier cataract surgery. This highlights the importance of a comprehensive and integrative approach to the management and treatment of DM1, going beyond addressing only the primary neuromuscular symptoms. More research is required to understand the underlying mechanisms contributing to these comorbidities in DM1 patients, which may inform preventative measures and guide improvements in patient care. [ABSTRACT FROM AUTHOR]

Aims Myotonic dystrophy Type 1 (DM1) is caused by the expansion of CTG repeats (CTGn) in the DM1 protein kinase (DMPK) gene, while it remains unclear whether CTGn may be associated with the incidence of cardiac events or sudden death in Japan as well as Europe. The aim of this study was to investigate the association between CTGn and cardiac involvements. Methods and results This cohort study included patients with DM1 who were retrospectively recruited from nine Japanese hospitals specializing in neuromuscular diseases. A total of 496 patients with DM1 who underwent a genetic test in the DMPK gene were analysed. Patients with congenital form or under 15 years old were excluded and patients were assigned into the quartiles. When we compared the incidence of cardiac events including advanced/complete atrioventricular block, pacemaker implantation, and ventricular tachycardias or mortality among four groups, patients with 1300 or longer CTGn experienced composite cardiac events [hazard ratio (HR): 3.19, 95% confidence interval (CI): 1.02–9.99, P = 0.014] more frequently and had significantly higher mortality rate (HR: 6.79, 95% CI: 2.05–22.49, P < 0.001) than those under 400 CTGn while the rate of sudden death was not significantly different. Conclusion Regarding the cardiac events and mortality in patients with DM1, patients with 1300 or longer CTGn are at especially high risk. [ABSTRACT FROM AUTHOR]

Abstract Background Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder that classically presents with symptoms associated with myotonia, early onset cataracts, and muscular weakness, although the presentation and pattern of disease progression is quite varied. Presenting symptoms are well documented among adults with DM1. However, less is known about the co-occurrence of symptoms over time. We aimed to use factor analysis to explore the correlation pattern of signs and symptoms (S/S) that emerged during the clinical course. Results Clinical records of 228 individuals with adult onset DM1 were abstracted using the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from a six-site cohort in the United States during an eight-year study period. Factor analysis was used to group the correlated S/S into latent factors. Three factors were identified. Group 1: ‘Facial Weakness/Myotonia’ includes the two most common S/S, as indicated by its name. Group 2: ‘Skeletal Muscle Weakness’ includes eight muscular S/S and is more frequently reported by males and those with older age at onset. Group 3: ‘Gastrointestinal distress/Sleepiness’ includes four non-muscular S/S and hand stiffness. The abstracted medical records reported that over 63% of individuals had S/S from all three groups. Associations of covariates with factor scores were also examined using linear regression. CTG repeat length was significantly positively associated with higher factor scores for all three factors. Conclusions This study identified three latent factors of S/S which accumulated during the clinical course of adult onset DM1.

Background: Myotonic dystrophy type 1 (DM1) is associated with progressive conduction disease. Furthermore, DM1 patients are at risk ventricular arrhythmias (VAs), although prediction remains difficult. The 2022 Heart Rhythm Expert Consensus Statement gives a IIb recommendation to the use of electrophysiology study (EPS) to risk-stratify patients for VAs. The utility of EPS in predicting the development of VAs, however, has not been explored in this patient population. Objective: The study sought to examine the natural history of DM1 patients with positive and negative ventricular stimulation (v-stim) during EPS. Methods: Patients with a history of DM1 undergoing EPS with associated v-stim from 2008 to present were retrospectively identified. Results: From 2008 to 2022, 26 consecutive DM1 patients presented for EPS with v-stim. Four v-stim protocols were positive for sustained or hemodynamically significant ventricular tachycardia (VT), one of which was induced with 600 doubles, the others with triple extrastimuli. A total of 22 of 26 subjects received a device implant, with 18 receiving permanent pacemakers and 4 implantable cardioverter-defibrillators. All 4 of the patients with positive v-stims underwent ICD implantation. After a mean of 5.7 years of follow-up, 7 patients had sustained VT, 6 of whom had negative v-stims. Of the 4 patients with positive v-stims, only 1 developed sustained VT in follow-up. Other than baseline QT interval at time of EPS, no baseline characteristics were significantly different between patients with and without subsequent VT. Conclusion: In this single center, v-stim in DM1 patients did not predict clinical VAs, as a vast majority of DM1 patients who developed VAs had negative v-stims.

Summary: Background: An optimal nutritional strategy has not been established for the patients with muscle atrophy. Moreover, acute critical illness causes drastic changes in skeletal muscles, complicating nutritional treatment. Here, we present a case of myotonic dystrophy suffered acute respiratory distress syndrome (ARDS). We aimed to describe the changes in skeletal muscle as well as nutrition therapy. Methods: A female in her 30s with myotonic dystrophy received mechanical ventilation for severe ARDS. Her respiratory status improved by day 15 of admission, but she developed severe weakness. We evaluated the cross-sectional area and mean computed tomography (CT) value of the psoas muscle at the level of the third lumber vertebra using abdominal CT scans performed on days 1 and 15. We also performed bioelectrical impedance analyses (BIA) on days 37 and 44. The patient received enteral nutrition from day 4, which was increased to administer 21.1 kcal/kg of energy and 1.05 g/kg of protein per day as the maintenance dose. Results: The cross-sectional area remarkably decreased from 8.59 cm2 on day 1–7.39 cm2 on day 15. The CT values decreased from 47.2 HU to 13.6 HU. BIA performed during the recovery phase showed impaired muscle quality (phase angle of 2.6 or 2.9°). The muscle volume was preserved with maintenance doses of enteral nutrition. Conclusion: Acute muscle volume loss and deteriorating muscle quality was observed during acute critical illness in a patient with myotonic dystrophy. The patient received a standard dose of energy and protein, and the muscle volume was preserved.

AbstractPurposeMaterials and methodsResultsConclusion\nIMPLICATIONS FOR REHABILITATIONTo identify the existing literature on experiences of living with adult-onset myotonic dystrophy type 1 (DM1) from people with adult-onset DM1, their caregivers and health care professionals.Following the framework of Arksey and O’Malley, a literature search was performed in five databases in October–November 2022. An updated search was conducted in December 2023. Studies were eligible if they reported on experiences related to living with DM1 from people with adult-onset DM1, caregivers or healthcare professionals. Qualitative, quantitative, and mixed method studies were included. Key findings were categorized using the International Classification of Functioning, Disability and Health (ICF) components.11 out of 1842 studies were included, of which five had a quantitative design, five had a qualitative design and one study had a mixed methods design. The studies reported on multiple experiences of living with adult-onset DM1 from the perspectives of people with the disease and their caregivers. All components of the ICF were reported in the studies; activity and participation and personal factors were the most reported.Adult-onset DM1 is a complex disease with great biopsychosocial impact making it challenging to live with for those diagnosed with DM1 as well as their caregivers. Issues with hands or arms, myotonia, fatigue, impaired sleep or daytime sleepiness, and symptoms of depression in everyday life should be addressed in the follow-up of people with adult-onset myotonic dystrophy type 1 (DM1) to facilitate increased participation in daily life.Challenges related to activity and participation should be addressed in the follow-up of people with adult-onset DM1 to help facilitate increased activity and participation in everyday life.Interventions targeting caregiver needs are necessary to help them cope with living with a person with adult-onset DM1 and to minimize the negative impact DM1 has on their lives.Issues with hands or arms, myotonia, fatigue, impaired sleep or daytime sleepiness, and symptoms of depression in everyday life should be addressed in the follow-up of people with adult-onset myotonic dystrophy type 1 (DM1) to facilitate increased participation in daily life.Challenges related to activity and participation should be addressed in the follow-up of people with adult-onset DM1 to help facilitate increased activity and participation in everyday life.Interventions targeting caregiver needs are necessary to help them cope with living with a person with adult-onset DM1 and to minimize the negative impact DM1 has on their lives. [ABSTRACT FROM AUTHOR]

Introduction: Chronic muscle pain is common in myotonic dystrophies (DM). Little is known about its pathophysiology. We aimed to investigate the characteristics of the neuropathic pain component contributing contributes to the pathogenesis of chronic pain in DM. Methods: Twenty-one DM1 and 32 DM2 patients completed pain questionnaires (Brief pain inventory--BPI, PAIN-DETECT, pain disability index--PDI) and underwent neurological examination, nerve conduction studies (NCS), quantitative sensory testing (QST, dorsum of the right hand and right thigh) and skin biopsy to determine the intraepidermal nerve fiber density (IENFD, distal and proximal site of lower extremity). NCS and QST results at the thigh were compared to 27 healthy controls and IENFD and QST at the dorsum of the hand to published reference values. Results: The sensory profile of DM2 patients was characterized by a loss in thermal and mechanical detection, while DM1 patients showed reduced mechanical and heat pain thresholds and higher mechanical pain sensitivity. Both DM groups showed pressure hyperalgesia. IENFD was reduced in 63% of DM1 patients and 50% of DM2. The slightly higher pain interference and disability found in DM2 was rather due to age difference than disease. Conclusion: Similar pain mechanisms likely occur in both DM1 and DM2, even though a tendency toward more pain sensitivity was observed in DM1 and more sensory loss in DM2. Both QST and reduced IENFD highlight the presence of peripheral nerve damage in DM. This must be considered for the best pain management strategies. [ABSTRACT FROM AUTHOR]

Background: Myotonic dystrophy type 1 (DM1) is a rare multisystemic genetic disorder with motor hallmarks of myotonia, muscle weakness and wasting. DM1 patients have an increased risk of falling of multifactorial origin, and proprioceptive and vestibular deficits can contribute to this risk. Abnormalities of muscle spindles in DM1 have been known for years. This observational cross-sectional study was based on the hypothesis of impaired cervical proprioception caused by alterations in the neck spindles. Methods: Head position sense was measured in 16 DM1 patients and 16 age- and gender-matched controls. A head-to-target repositioning test was requested from blindfolded participants. Their head was passively rotated approximately 30° leftward or rightward and flexed or extended approximately 25°. Participants had to replicate the imposed positions. An optoelectronic system was adopted to measure the angular differences between the reproduced and the imposed positions (joint position error, JPE, °) concerning the intended (sagittal, horizontal) and unintended (including the frontal) planar projections. In DM1 patients, JPEs were correlated with clinical and balance measures. Static balance in DM1 patients was assessed through dynamic posturography. Results: The accuracy and precision of head repositioning in the intended sagittal and horizontal error components did not differ between DM1 and controls. On the contrary, DM1 patients showed unintended side-bending to the left and the right: the mean [95%CI] of frontal JPE was −1.29° [−1.99°, −0.60°] for left rotation and 0.98° [0.28°, 1.67°] for right rotation. The frontal JPE of controls did not differ significantly from 0° (left rotation: 0.17° [−0.53°, 0.87°]; right rotation: −0.22° [−0.91°, 0.48°]). Frontal JPE differed between left and right rotation trials (p < 0.001) only in DM1 patients. No correlation was found between JPEs and measures from dynamic posturography and clinical scales. Conclusions: Lateral head bending associated with head rotation may reflect a latent impairment of neck proprioception in DM1 patients. [ABSTRACT FROM AUTHOR]

Purpose: To perform a scoping review to investigate the psychosocial impact of having an altered facial expression in five neurological diseases. Methods: A systematic literature search was performed. Studies were on Bell's palsy, facioscapulohumeral muscular dystrophy (FSHD), Moebius syndrome, myotonic dystrophy type 1, or Parkinson's disease patients; had a focus on altered facial expression; and had any form of psychosocial outcome measure. Data extraction focused on psychosocial outcomes. Results: Bell's palsy, myotonic dystrophy type 1, and Parkinson's disease patients more often experienced some degree of psychosocial distress than healthy controls. In FSHD, facial weakness negatively influenced communication and was experienced as a burden. The psychosocial distress applied especially to women (Bell's palsy and Parkinson's disease), and patients with more severely altered facial expression (Bell's palsy), but not for Moebius syndrome patients. Furthermore, Parkinson's disease patients with more pronounced hypomimia were perceived more negatively by observers. Various strategies were reported to compensate for altered facial expression. Conclusions: This review showed that patients with altered facial expression in four of five included neurological diseases had reduced psychosocial functioning. Future research recommendations include studies on observers' judgements of patients during social interactions and on the effectiveness of compensation strategies in enhancing psychosocial functioning. IMPLICATIONS FOR REHABILITATION: Negative effects of altered facial expression on psychosocial functioning are common and more abundant in women and in more severely affected patients with various neurological disorders. Health care professionals should be alert to psychosocial distress in patients with altered facial expression. Learning of compensatory strategies could be a beneficial therapy for patients with psychosocial distress due to an altered facial expression. [ABSTRACT FROM AUTHOR]

• A critical literature review of case reports on statins-induced side effects in various hereditary myopathies. • Setting criteria to assess case reports of statin myotoxicity in hereditary myopathies. • Identification of myopathies with high risk for statin usage (MELAS and other mitochondrial disorders, myotonic dystrophy type 2, McArdle disease). • Suggesting practical management of hyperlipidemia in hereditary myopathies. Hyperlipidemia is not uncommon in patients with hereditary myopathies who get older and also in several conditions in which it is frequently observed. Thus, using the common cholesterol reducing medications of the stains group could be considered. However, the side effects of these drugs include myalgia, myopathy and rhabdomyolysis typically associated with high serum creatine kinase (CK). Because high CK levels are very frequently found in hereditary myopathies, physicians are reluctant to use statins in such patients. Reviewing the literature about statin side effects in hereditary myopathies does not provide a clear evidence about the true risk of these drugs. This review critically describes the reported cases of statin side effects in several genetic myopathies and suggests some guidelines for conditions that are contra indicated for statin usage (particularly in mitochondrial disorders, metabolic myopathies, myotonic dystrophy type 2). Possible solutions to the dilemma of whether to use statins in hereditary myopathies are discussed (prescribing other cholesterol lowering agents and a carefully monitored treatment initiation of statins). [ABSTRACT FROM AUTHOR]

Background: Myotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy disease types 1 (DM1) and 2 (DM2) cover a similar spectrum of symptoms, more pronounced clinical and brain alterations have been described in DM1. Here, we investigated brain volumetric and white matter alterations in both disease types and compared to healthy controls (HC). Methods: MRI scans were obtained from 29 DM1, 27 DM2, and 56 HC. We assessed macro- and microstructural brain changes by surface-based analysis of cortical thickness of anatomical images and tract-based spatial statistics of fractional anisotropy (FA) obtained by diffusion-weighted imaging, respectively. Global MRI measures were related to clinical and neuropsychological scores to evaluate their clinical relevance. Results: Cortical thickness was reduced in both patient groups compared to HC, showing similar patterns of regional distribution in DM1 and DM2 (occipital, temporal, frontal) but more pronounced cortical thinning for DM1. Similarly, FA values showed a widespread decrease in DM1 and DM2 compared to HC. Interestingly, FA was significantly lower in DM1 compared to DM2 within most parts of the brain. Conclusion: Comparisons between DM1 and DM2 indicate a more pronounced cortical thinning of grey matter and a widespread reduction in microstructural integrity of white matter in DM1. Future studies are required to unravel the underlying and separating mechanisms for the disease courses of the two types and their neuropsychological symptoms. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Early diagnosis of a chronic neuromuscular disease such as muscular dystrophy (MD) generally excludes an individual from active‐duty military service. However, it is not known whether veterans are sometimes diagnosed with milder forms of MD at a later timepoint. We aimed to determine the prevalence of MD in a veterans health system. Methods: We abstracted clinical and genetic test data on patients who received care for a diagnosis of MD at the North Florida/South Georgia Veterans Health System between 2008 and 2021. We then determined which of these individuals would meet criteria for a definite diagnosis of MD, based on electrodiagnostic testing, muscle biopsy, and genetic testing of the individual or an affected first degree relative. Results: We identified 12 patients with definite MD and 36 with possible or probable MD. The definite cases included myotonic dystrophy type 1 (4), myotonic dystrophy type 2 (3), oculopharyngeal MD (2), Becker MD (1), distal MD (1), and facioscapulohumeral MD (1). At least five of the cases classified as definite developed symptoms after discharge from active duty. Discussion: Clinicians who care for veterans should be knowledgeable about, and have access to, diagnostic testing and treatment options for MD. When conducting MD surveillance, it is important to include veterans health systems as a data source. Mild cases of MD and those of later onset appear to be compatible in some cases with successful completion of military service. [ABSTRACT FROM AUTHOR]

• Maximal hip and knee extension muscle strength increased by the training program. • Apathy and anxiety decreased after the 12-week training. • Muscle hypertrophy was induced by resistance training. Myotonic dystrophy type 1 (DM1) is a hereditary disease characterized by muscular impairments. Fundamental and clinical positive effects of strength training have been reported in men with DM1, but its impact on women remains unknown. We evaluated the effects of a 12-week supervised strength training on physical and neuropsychiatric health. Women with DM1 performed a twice-weekly supervised resistance training program (3 series of 6–8 repetitions of squat, leg press, plantar flexion, knee extension, and hip abduction). Lower limb muscle strength, physical function, apathy, anxiety and depression, fatigue and excessive somnolence, pain, and patient-reported outcomes were assessed before and after the intervention, as well as three and six months after completion of the training program. Muscle biopsies of the vastus lateralis were also taken before and after the training program to assess muscle fiber growth. Eleven participants completed the program (attendance: 98.5 %). Maximal hip and knee extension strength (p < 0.006), all One-Repetition Maximum strength measures (p < 0.001), apathy (p = 0.0005), depression (p = 0.02), pain interference (p = 0.01) and perception of the lower limb function (p = 0.003) were significantly improved by training. Some of these gains were maintained up to six months after the training program. Strength training is a good therapeutic strategy for women with DM1. [ABSTRACT FROM AUTHOR]

Using virtual reality (VR) for Muscular Dystrophy (MD) rehabilitation promises to be a novel therapeutic approach, potentially enhancing motor learning, functional outcomes, and overall quality of life. This systematic review primarily aimed to provide a comprehensive summary of the current understanding regarding the application of VR in supporting MD rehabilitation. A systematic search was performed in PubMed, Scopus, Cochrane Library, and Web of Science to identify relevant articles. The inclusion criteria encompassed studies involving individuals diagnosed with MD who underwent VR interventions, with a primary focus on assessing functional improvement. Methodological quality of the studies was assessed by using the Physiotherapy Evidence Database (PEDro) scale. Seven studies, involving 440 individuals with Duchenne Muscular Dystrophy (DMD), were included in the review. Among these studies, six primarily explored the motor learning potential of VR, while one study investigated the impact of VR training on functional abilities. In conclusion, the qualitative synthesis supports VR-based interventions' potential positive effects on motor learning, performance improvement, and functional outcomes in individuals with DMD. However, current usage mainly focuses on assessing the potential mechanisms' benefits, suggesting the importance of expanding clinical adoption to harness their therapeutic potential for MD patients. [ABSTRACT FROM AUTHOR]

Background: Severity and nature of cognitive impairments in Myotonic dystrophy type 1 (DM1) are heterogeneous among studies. We hypothesized that this heterogeneity is explained by different cognitive profiles in DM1, with different clinical, biological and behavioral features. Methods: Adult patients with genetically proven DM1 underwent a clinical, neuropsychological and behavioral assessment. We conducted a k-means clustering analysis on 9 cognitive tests representative of different domains (verbal/non-verbal episodic memory, visuo-constructive abilities, visual gnosis, executive functions, information processing speed). Results: We included 124 DM1 patients. Mean age was 45.1 ± 13.5 years [19.8–73.2], mean age of onset was 30.4 ± 15.7 years [5–72], and mean CTG triplets' expansion size was 489.7 ± 351.8 [50–1600]. We found 3 cognitive clusters, including, respectively, 84, 29 and 11 patients. The first cluster included patients with more preserved cognitive functions; the second included patients with worse cognitive performances which predominate on executive functions; and the third even more pronounced and diffuse cognitive deficits. Younger patients, with a more recent DM1 clinical onset, higher educational level were more frequently classified in the cluster with more preserved cognitive functions. There were no significant differences between clusters regarding CTG triplets' expansion, neither age at DM1 onset, nor most of behavioral measures. Conclusions: We found different cognitive profiles in our DM1 population, which seem influenced by age and DM1 duration. Our findings may explain the heterogeneity of studies about cognition in DM1, and suggest a potential neurodegenerative mechanism in DM1 adults. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, yet there are currently no disease-modifying treatments. Disrupted miRNA expressions may lead to dysregulation of target mRNAs and dysfunction involved in DM1 pathogenic mechanism. We used microarray platforms to examine the miRNA/mRNA expression profiles in skeletal muscle biopsies derived from DM1 patients and matched controls. Bioinformatics analysis and dual-luciferase reporter assay were conducted to provide insight into miRNA-mRNA regulatory networks altered in DM1. Twenty-three differentially expressed miRNAs and 135 differentially expressed genes were identified. qPCR confirmed that miR-3201, myogenic factor 5 (MYF5), myogenic differentiation 1 (MYOD1), CUGBP, Elav-like family member 1 (CELF1), and CELF2 were significantly up-regulated, while miR-196a, miR-200c, and miR-146a were significantly down-regulated. Enriched functions and pathways such as multicellular organismal development, RNA splicing, cell differentiation, and spliceosome are relevant to DM1. The miRNA-mRNA interaction network revealed that miR-182, miR-30c-2, and miR-200c were the critical nodes that potentially interacted with hub genes. Luciferase reporter assay confirmed the direct interaction between miR-196a and CELF2. Those results implied that the observed miRNA/mRNA dysregulation could contribute to specific functions and pathways related to DM1 pathogenesis, highlighting the dysfunction of miR-196a and CELF2. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mexiletine, an antiarrhythmic agent, can relieve skeletal muscle myotonic symptoms. • In France, mexiletine can be used compassionately for myotonic dystrophy (MD). • An expert group has produced an algorithm for mexiletine use in patients with MD. • Patients with MD need close cardiac monitoring before and during mexiletine use. In France, mexiletine – a class I antiarrhythmic drug – can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy. [ABSTRACT FROM AUTHOR]

IntroductionNon-invasive evaluation of myocardial tissue is a major goal of cardiac imaging. This is the case of myocardial fibrosis which is crucial in many myocardial diseases. Cardiac extracellular volume (ECV) was shown to indicate myocardial fibrosis and early cardiac involvement. With this study, our objective is to evaluate ECV measured with cardiac magnetic resonance (CMR) in patients with myotonic dystrophy type 1 (DM1) and 2 (DM2) as potential imaging biomarkers of subclinical cardiac pathology, and its relationship with demographic and clinical parameters, ECG-derived measures of cardiac conduction, and neuromuscular performance status.Materials and methodsWe retrospectively analyzed 18 DM1 patients and 4 DM2 patients without apparent cardiac disease who had CMR at our center. Differences between independent distributions were evaluated using Mann–Whitney U test, while correlations were evaluated using Spearman’s ρ.ResultsGlobal ECV in DM1 patients (median 28.36; IQR 24.81–29.77) was significantly higher (p = 0.0141) than in DM2 patients (median 22.93; IQR 21.25–24.35), and than that reported in literature in healthy subjects (p = 0.0374; median 25.60; IQR 19.90–31.90). Septal ECV was significantly higher (p = 0.0074) in DM1 (median 27.37; IQR 25.97–29.74) than in DM2 patients (median 22.46; 21.57–23.19). Global ECV showed a strong, positive correlation with septal ECV (ρ = 0.9282, p

ABSTRACT Background Myotonic Dystrophy type 1 (DM1) is an autosomal dominant disease with anticipation due to increased number of CTG repeats in the DMPK gene. Methods This retrospective, cohort study in Iceland assessed prevalence of DM1, molecular pathology, and patient ascertainment. Data was collected from all major hospitals in Iceland, Medical Director of Health, and independent clinics. Cohort criteria were diagnosis of DM1 on January 1, 2021, or time of death. Population‐based Icelandic Genealogy Database of the Genetical Committee at the University of Iceland was used for genealogy. Results In Iceland, 221 individuals, including 19 obligate carriers, had been diagnosed with DM1 of which 144 were alive giving a point prevalence of 39 per 100,000 (four times the world average of 9.3). Genealogy analysis identified 45 first‐degree families. Age‐adjusted prevalence ranged between 11 and 66 per 100,000. Average potential years of life lost were 20.5 per person. Where information was available, 63% of ascertainment was based on family history in cascade testing. Conclusion The differences in age‐adjusted prevalence suggest that the overall point prevalence is an underestimation due to underdiagnosis in younger age groups and lethality in oldest age group. Our data supports use of cascade testing to improve DM1 ascertainment.

Abstract Background Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. Methods We compared changes in NMJs and activity-dependent signalling pathways in HSA LR and Mbnl1 ΔE3/ΔE3 mice, two established mouse models of DM1. Results Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1 ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation. Conclusions Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.

Myotonic dystrophy type 1 (DM1) is a multisystem trinucleotide repeat expansion disorder usually referred to the department of neurology with complaints of progressive muscle weakness and myotonia. This article reported a 33-year-old female patient with DM1 presenting with acute respiratory failure.Muscle biopsy in vastus lateralis showed significantly increased internal nuclei. Genetic test show CTG repeat expansions with the size of (847±76) in dystrophia myotonica protein kinase (DMPK) gene on chromosome 19. This case report broadens the clinician′s understanding of the atypical clinical manifestations of DM1, so as to avoid missed diagnosis and misdiagnosis.

Background: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. Methods: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1. Results: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation. Conclusions: Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the recognition of DM as a neurological disorder. Cognitive impairment is a central nervous system condition that has been observed in various forms of DM. Neuroimaging studies have increasingly linked DM to alterations in white matter (WM) integrity and highlighted the relationship between cognitive impairment and abnormalities in WM structure. This review aims to summarize investigations into cognitive impairment and brain abnormalities in individuals with DM and to elucidate the correlation between these factors and the potential underlying mechanisms contributing to these abnormalities. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type I (MDI) is the most common muscular dystrophy in adults. The main objectives of this study were to determine the prevalence of MDI in the Community of Madrid (CM) (Spain) and to analyze the use of public healthcare services; a population-based cross-sectional descriptive study was carried out on patients with MDI in CM and data were obtained from a population-based registry (2010–2017). A total of 1101 patients were studied (49.1% women) with average age of 47.8 years; the prevalence of MDI was 14.4/100,000 inhabitants. In the women lineal regression model for hospital admissions, being in the fourth quartile of the deprivation index, was a risk factor (regression coef (rc): 0.80; 95%CI 0.25–1.37). In the overall multiple lineal regression model for primary health care (PHC) attendance, being a woman increased the probability of having a higher number of consultations (rc: 3.99; 95%CI: 3.95–5.04), as did being in the fourth quartile of the deprivation index (rc: 2.10; 95%CI: 0.58–3.63); having received influenza vaccines was a protective factor (rc: −0.46; 95%CI: −0.66–(−0.25)). The prevalence of MDI in the CM is high compared to other settings. Moreover, having any level of risk stratification of becoming ill (high, medium or low) has a positive association with increased PHC consultations and hospital admissions. [ABSTRACT FROM AUTHOR]

Purpose: Muscular dystrophy is a group of heterogeneous diseases causing progressive muscle weakness and atrophy. Many types have been defined, including Duchenne/Becker, myotonic, limb-girdle, congenital, and facioscapulohumeral muscular dystrophies. This study aims to present the first patient with both a homozygous CAPN3 mutation and a CCTG expansion in the CNBP gene, which suggests the co-occurrence of two diseases in a single patient. Case description: Homozygous pathogenic variant c.550delA (p.Thr184ArgfsTer36) in the CAPN3 gene, as well as a heterozygous expansion of a CCTG repeat of the CNBP gene, were identified in a single patient. Segregation analysis showed both maternal and paternal heterozygous carriers for CAPN3 mutation, and a maternally inherited CNBP expansion. Comment: In general, the co-occurrence of two diseases in a single patient is considered as uncommon, although possible, and therefore it should be taken into consideration in the populations with a relatively high prevalence of myotonic dystrophy type 2. [ABSTRACT FROM AUTHOR]

Aim: To present a patient with an extremely rare combination of myotonic dystrophy 1 and multiple sclerosis. Myotonic dystrophy type 1 is the most common inherited muscular dystrophy in adults, while multiple sclerosis is a demyelinating autoimmune disease of the central nervous system caused by the interaction of genetic and environmental factors. The co-occurrence of these two diseases has only been described in one case in world literature. Case report: A 31-year-old male patient presented with repeated episodes of spastic left hemiparesis, ataxia, dysarthria, and dyplopia, as well as mental deterioration and progressive muscle atrophy. DNA analysis revealed myotonic dystrophy 1, delayed visual evoked potentials, the presence of oligoclonal bands of immunoglobulin G in the cerebrospinal fluid, and MRI findings of the brain were suggestive of multiple sclerosis. After administration of corticosteroids, the patient’s condition improved, and some symptoms resolved. Conclusion: All clinical and laboratory findings suggest that the patient suffers from both listed diseases. Since this is an extremely rare case, it can certainly arouse scientific and professional interest. [ABSTRACT FROM AUTHOR]

Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats. [ABSTRACT FROM AUTHOR]

IntroductionChronic muscle pain is common in myotonic dystrophies (DM). Little is known about its pathophysiology. We aimed to investigate the characteristics of the neuropathic pain component contributing contributes to the pathogenesis of chronic pain in DM.MethodsTwenty-one DM1 and 32 DM2 patients completed pain questionnaires (Brief pain inventory–BPI, PAIN-DETECT, pain disability index–PDI) and underwent neurological examination, nerve conduction studies (NCS), quantitative sensory testing (QST, dorsum of the right hand and right thigh) and skin biopsy to determine the intraepidermal nerve fiber density (IENFD, distal and proximal site of lower extremity). NCS and QST results at the thigh were compared to 27 healthy controls and IENFD and QST at the dorsum of the hand to published reference values.ResultsThe sensory profile of DM2 patients was characterized by a loss in thermal and mechanical detection, while DM1 patients showed reduced mechanical and heat pain thresholds and higher mechanical pain sensitivity. Both DM groups showed pressure hyperalgesia. IENFD was reduced in 63% of DM1 patients and 50% of DM2. The slightly higher pain interference and disability found in DM2 was rather due to age difference than disease.ConclusionSimilar pain mechanisms likely occur in both DM1 and DM2, even though a tendency toward more pain sensitivity was observed in DM1 and more sensory loss in DM2. Both QST and reduced IENFD highlight the presence of peripheral nerve damage in DM. This must be considered for the best pain management strategies.

Background: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3′ untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSALR mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction in vivo. Methods: By means of recombinant AAV murine MSI2 was overexpressed in neonates HSALR mice skeletal muscle to induce DM1-like phenotypes. Results: Sustained overexpression of the murine MSI2 protein in HSALR neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of MBNL1, MBNL2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression. Conclusions: Globally, molecular, histological, and functional data from these experiments in the HSALR mouse model confirms the pathological role of MSI2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.

Abstract Background Engaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them. Methods Dyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes. Results The issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants. Conclusions Ongoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

Objective: Electrodiagnostic testing is an important screening test for myotonic dystrophy type 1 (DM1). Although myotonic discharges are observed on electromyography in cases of DM1, it is difficult to distinguish DM1 from other myotonic disorders clinically. In the present study, afterdischarges, another type of pathological potential revealed by electrodiagnostic testing, were analyzed, and their role in distinguishing DM1 from other myotonic disorders was explored. Methods: Data from 33 patients with myotonic discharges on electromyography were analyzed retrospectively. According to gene testing, the patients were divided into DM1 (n = 20) and non-DM1 myotonia (n = 13) groups. Afterdischarges were investigated by retrospectively evaluating the electrodiagnostic findings of motor nerve conduction studies, F-waves, and repetitive nerve stimulations. Results: Afterdischarges were observed in 17 of the 20 patients with DM1, with an occurrence rate of approximately 85%. However, afterdischarges were absent in all patients with non-DM1 myotonia. There were significant differences in the occurrence rate between the two groups (P < 0.01). Conclusion: Afterdischarges may serve as a suggestive role in clinical diagnosis of DM1. The discovery that DM1 can present with afterdischarges may pave a new way to study the pathogenesis of DM1. [ABSTRACT FROM AUTHOR]

Background: Engaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them. Methods: Dyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes. Results: The issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants. Conclusions: Ongoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families. Plain Language Summary: Why is this important?: Including the viewpoint of people living with chronic diseases when developing new therapeutics helps address their specific needs and improve their quality of life. This is very important for rare diseases, where individuals and their families face many challenges getting information, treatment, and support. What did we do?: Dyne Therapeutics, a company focused on developing potential medicines for rare muscle diseases, actively involved individuals living with Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) in their drug development process. Dyne organized workshops for individuals and families living with DMD and DM1 and participated in community advisory boards to gather input from patient advocacy organization leaders. How did this help?: Partnering with individuals and families living with DMD and DM1 helped Dyne improve clinical trial design and reduce the difficulties affected individuals and their families face when participating in these trials. This valuable feedback has allowed Dyne to design clinical trials to better address the needs of those living with DMD and DM1. [ABSTRACT FROM AUTHOR]

Using virtual reality (VR) for Muscular Dystrophy (MD) rehabilitation promises to be a novel therapeutic approach, potentially enhancing motor learning, functional outcomes, and overall quality of life. This systematic review primarily aimed to provide a comprehensive summary of the current understanding regarding the application of VR in supporting MD rehabilitation. A systematic search was performed in PubMed, Scopus, Cochrane Library, and Web of Science to identify relevant articles. The inclusion criteria encompassed studies involving individuals diagnosed with MD who underwent VR interventions, with a primary focus on assessing functional improvement. Methodological quality of the studies was assessed by using the Physiotherapy Evidence Database (PEDro) scale. Seven studies, involving 440 individuals with Duchenne Muscular Dystrophy (DMD), were included in the review. Among these studies, six primarily explored the motor learning potential of VR, while one study investigated the impact of VR training on functional abilities. In conclusion, the qualitative synthesis supports VR-based interventions’ potential positive effects on motor learning, performance improvement, and functional outcomes in individuals with DMD. However, current usage mainly focuses on assessing the potential mechanisms’ benefits, suggesting the importance of expanding clinical adoption to harness their therapeutic potential for MD patients.

The study has developed a model splicing construct assay system based on splicing misregulation, one of the major molecular features associated with myotonic dystrophy. The splicing construct assay has double reporters for intron 2 splicing in chloride channel (CLCN1). The CLCN1 transgene splicing construct assay was used to transfect wild type and DM fibroblast cell lines and the clones generated showed that it enabled quantification of splicing efficiency in transgene construct. Validation of the DM fibroblasts containing transgene splicing construct was performed by differentiating the DM fibroblasts into myoblasts which exhibited a switch in CLCN1 splicing construct which was consistent with that associated with myotonic dystrophy (DM) condition. The myoblast derived from fibroblasts cell-based gene-splicing assay was subsequently applied in therapeutic screening in small throughput screens of 113 compounds which identified Protein Kinase C inhibitors- hypericin and Ro-31-8220 as potential therapeutic agents. The CLCN1 gene-splicing assay is a good model system for application in therapeutic screening in myotonic dystrophy because its double reporters facilitated quantification of effect putative drug on correction of misregulated splicing.

Summary: Background: Myotonic dystrophy type 1 (DM1) is a devastating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene, which subsequently triggers toxic RNA expression and dysregulated splicing. In a preclinical study, we demonstrated that erythromycin reduces the toxicity of abnormal RNA and ameliorates the aberrant splicing and motor phenotype in DM1 model mice. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at three centres in Japan to translate preclinical findings into practical applications in patients with DM1 by evaluating the safety and efficacy of erythromycin. Between Nov 29, 2019, and Jan 20, 2022, a total of 30 adult patients with DM1 were enrolled and randomly assigned in a 1:2:2 ratio to receive either placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks. The primary outcome included the safety and tolerability of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-min walk test results, muscle strength, and serum creatinine kinase (CK) values. This trial is registered with the Japan Registry of Clinical Trials, jRCT2051190069. Findings: Treatment-related gastrointestinal symptoms occurred more frequently in the erythromycin group, but all adverse events were mild to moderate and resolved spontaneously. No serious safety concerns were identified. The CK levels from baseline to week 24 decreased in the overall erythromycin group compared with the placebo group (mean change of −6.4 U/L [SD 149] vs +182.8 [SD 228]), although this difference was not statistically significant (p = 0.070). Statistically significant improvements in the overall erythromycin treated groups compared to placebo were seen for two of the eleven splicing biomarkers that were each evaluated in half of the trial sample. These were MBNL1 (p = 0.048) and CACNA1S (p = 0.042). Interpretation: Erythromycin demonstrated favourable safety and tolerability profiles in patients with DM1. A well-powered phase 3 trial is needed to evaluate efficacy, building on the preliminary findings from this study. Funding: Japan Agency for Medical Research and Development.

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the DMPK gene that generates toxic RNA with a myriad of downstream alterations in RNA metabolism. A key consequence is the sequestration of alternative splicing regulatory proteins MBNL1/2 by expanded transcripts in the affected tissues. MBNL1/2 depletion interferes with a developmental alternative splicing switch that causes the expression of fetal isoforms in adults. Boosting the endogenous expression of MBNL proteins by inhibiting the natural translational repressors miR-23b and miR-218 has previously been shown to be a promising therapeutic approach. We designed antimiRs against both miRNAs with a phosphorodiamidate morpholino oligonucleotide (PMO) chemistry conjugated to cell-penetrating peptides (CPPs) to improve delivery to affected tissues. In DM1 cells, CPP-PMOs significantly increased MBNL1 levels. In some candidates, this was achieved using concentrations less than two orders of magnitude below the median toxic concentration, with up to 5.38-fold better therapeutic window than previous antagomiRs. In HSALR mice, intravenous injections of CPP-PMOs improve molecular, histopathological, and functional phenotypes, without signs of toxicity. Our findings place CPP-PMOs as promising antimiR candidates to overcome the treatment delivery challenge in DM1 therapy.

Background: Rest-activity rhythm disturbances have been reported in myotonic dystrophy type 1 (DM1) but no study has assessed its relationship with apathy and light exposure using actigraphy. Methods: Thirty-three DM1 patients wore an actigraph for two consecutive weeks. The Lille Apathy Rating Scale was used to assess apathy. Actigraphy was used to characterize sleep, activity, and light exposure and nonparametric analysis was performed to characterize intraday variability (IV), interday stability (IS), least active five-hour period (L5), most active ten-hour period (M10), and relative amplitude (RA). Results: Apathy was found in 42.4% of patients. Patients with apathy have a larger number of CTG repeat than those without (774 vs 381, p

• Suitability of Respicheck and ESS for IMT monitoring not met. • No significant correlation between PROMs and lung function in subgroup analysis. • Significant improvements in respiratory function assessments after IMT. • High incidence of hypoventilation symptoms in DM1. 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. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy, also referred myotonic muscular dystrophy, is an autosomal dominant, slowly progressive, multisystem disease characterized by skeletal muscle weakness, wasting, and myotonia. A hybrid tumor of odontogenic apparatus is a lesion showing combined histopathological characteristics of two or more previously recognized odontogenic tumors and/or cysts of different categories. We, therefore, report a case of hybrid tumor (adenomatoid odontogenic tumor associated with calcifying cystic odontogenic tumor) in a myotonic dystrophic patient. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Ultrasound imaging of muscle tissue conventionally results in two‐dimensional sampling of tissue. For heterogeneously affected muscles, a sampling error using two‐dimensional (2D) ultrasound can therefore be expected. In this study, we aimed to quantify and extend ultrasound imaging findings in neuromuscular disorders by using three‐dimensional quantitative muscle ultrasound (3D QMUS). Methods: Patients with facioscapulohumeral dystrophy (n = 31) and myotonic dystrophy type 1 (n = 16) were included in this study. After physical examination, including Medical Research Council (MRC) scores, the tibialis anterior muscle was scanned with automated ultrasound. QMUS parameters were calculated over 15 cm of the length of the tibialis anterior muscle and were compared with a healthy reference data set. Results: With 3D QMUS local deviations from the healthy reference could be detected. Significant Pearson correlations (P <.01) between MRC score and QMUS parameters in male patients (n = 23) included the mean echo intensity (EI) (0.684), the standard deviation of EI (0.737), and the residual attenuation (0.841). In 91% of all patients, mean EI deviated by more than 1 standard deviation from the healthy reference. In general, the proportion of muscle tissue with a Z score >1 was about 50%. Discussion: In addition to mean EI, multiple QMUS parameters reported in this study are potential biomarkers for pathology. Besides a moderate correlation of mean EI with muscle weakness, two other parameters showed strong correlations: standard deviation of EI and residual attenuation. Local detection of abnormalities makes 3D QMUS a promising method that can be used in research and potentially for clinical evaluation. [ABSTRACT FROM AUTHOR]

• Myotonic dystrophy type 1 patients often present with respiratory insufficiency. • Sleep apnea is very common in myotonic dystrophy type 1 patients. • Home mechanical ventilation is frequently needed in myotonic dystrophy patients. • Low compliance with home mechanical ventilation often occurs in myotonic dystrophy. • Respiratory features cannot predict home mechanical ventilation treatment failure. Chronic respiratory insufficiency is common in patients with myotonic dystrophy type 1 (DM1) and can be treated with noninvasive home mechanical ventilation (HMV). HMV is not always tolerated well resulting in low treatment adherence. We aimed to analyze if baseline respiratory characteristics such as pulmonary function, level of pCO 2 and presence of sleep apnea are associated with HMV treatment adherence in DM1 patients. Pulmonary function testing, polysomnography and blood gas measurement data of DM1 patients were retrospectively collected. Initiation of HMV and treatment adherence after one year was documented. Patients with low treatment adherence (average daily use of HMV <5 h) were grouped with patients that discontinued HMV and compared with patients with high treatment adherence (average daily use of HMV >5 h). HMV was initiated in 101 patients. After one year, 58 patients had low treatment adherence. There were no differences between the low and high treatment adherence group regarding the respiratory characteristics. None of the included predictors (gender, age, body mass index, cytosine-thymine-guanine repeat length, FVC, daytime pCO 2 , bicarbonate, nighttime pCO 2 , nighttime base excess, apnea-hypopnea index and mean saturation during sleep) was able to significantly predict high treatment adherence. In conclusion, the respiratory characteristics are not associated with treatment adherence with HMV in DM1 patients and cannot be used to identify patients at risk for low HMV treatment adherence. [ABSTRACT FROM AUTHOR]

Abstract Reduced brain volume including atrophy in grey and white matter is commonly seen in myotonic dystrophy type 1 (DM1). DM1 is caused by an expansion of CTG trinucleotide repeats in the 3’ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. Mutant DMPK mRNA containing expanded CUG RNA (DMPK-CUGexp) sequesters cytoplasmic MBNL1, resulting in morphological impairment. How DMPK-CUGexp and loss of MBNL1 cause histopathological phenotypes in the DM1 brain remains elusive. Here, we show that BDNF-TrkB retrograde transport is impaired in neurons expressing DMPK-CUGexp due to loss of cytoplasmic MBNL1 function. We reveal that mature BDNF protein levels are reduced in the brain of the DM1 mouse model EpA960/CaMKII-Cre. Exogenous BDNF treatment did not rescue impaired neurite outgrowth in neurons expressing DMPK-CUGexp, whereas overexpression of the cytoplasmic MBNL1 isoform in DMPK-CUGexp-expressing neurons improved their responsiveness to exogenous BDNF. We identify dynein light chain LC8-type 2, DYNLL2, as an MBNL1-interacting protein and demonstrate that their interaction is RNA-independent. Using time-lapse imaging, we show that overexpressed MBNL1 and DYNLL2 move along axonal processes together and that MBNL1-knockdown impairs the motility of mCherry-tagged DYNLL2, resulting in a reduced percentage of retrograde DYNLL2 movement. Examination of the distribution of DYNLL2 and activated phospho-TrkB (pTrkB) receptor in EpA960/CaMKII-Cre brains revealed an increase in the postsynaptic membrane fraction (LP1), indicating impaired retrograde transport. Finally, our neuropathological analysis of postmortem DM1 tissue reveals that reduced cytoplasmic MBNL1 expression is associated with an increase in DYNLL2 and activated pTrkB receptor levels in the synaptosomal fraction. Together, our results support that impaired MBNL1-mediated retrograde BDNF-TrkB signaling may contribute to the histopathological phenotypes of DM1.

We present a unique case of a 44-year-old woman who presented at 29 weeks' gestation with proximal limb pain and elevated creatine kinase. This occurred in the background of premature cataracts, atrial fibrillation and abnormal liver function. Clinical, pathological and neurodiagnostic findings supported a diagnosis of myotonic dystrophy, confirmed by genetic testing which revealed dystrophia myotonica protein kinase gene expansion. Muscle biopsy found both recent necrotising and chronic myopathic processes. Following delivery, the mother's myalgia resolved and creatine kinase quickly declined. The fetus was diagnosed with congenital myotonic dystrophy. We review the impact of myotonic dystrophy on pregnancy and discuss potential explanations for this patient's clinical course. This case emphasises the importance of considering myotonic dystrophy as a differential diagnosis in the right clinical context and the need for pre-pregnancy assessment and genetic counselling in women with known myotonic dystrophy. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Myotonic dystrophies (DMs) are autosomal dominant diseases in which expression of a mutant expanded repeat mRNA leads to abnormal splicing of downstream effector genes thought to be responsible for their multisystem involvement. Cancer risk and cancer‐related deaths are increased in DM patients relative to the general population. We aimed at determining the frequency and type of cancers in both DM1 and DM2 vs a non‐DM muscular dystrophy cohort. Methods: A retrospective, cross‐sectional study was carried out on patients with genetically confirmed DM1, DM2, facioscapulohumeral muscular dystrophy (FSHD), and oculopharyngeal muscular dystrophy (OPMD) at our institutions from 2000 to 2020. Results: One hundred eighty‐five DM1, 67 DM2, 187 FSHD, and 109 OPMD patients were included. Relative to non‐DM, DM patients had an increased cancer risk that was independent of age and sex. Specifically, an increased risk of sex‐related (ovarian) and non–sex‐related (non‐melanoma skin, urological, and hematological) cancers was observed in DM1 and DM2, respectively. The length of CTG repeat expansion was not associated with cancer occurrence in the DM1 group. Discussion: In addition to current consensus‐based care recommendations, our findings prompt consideration of screening for skin, urological, and hematological cancers in DM2 patients, and screening of ovarian malignancies in DM1 female patients. See Editorial on pages 101–102 in this issue. [ABSTRACT FROM AUTHOR]