Nutritional Issues among Children with Duchenne Muscular Dystrophy-Incidence of Deficiency and Excess Body Mass.

The progression of Duchenne muscular dystrophy (DMD)requires the assessment of nutritional disturbances at each stage of the disease. The purpose of this study was to assess the nutritional status in various ages of boys with DMD using screening and in-depth evaluation methods. Body composition by Dual X-ray Absorptiometry (DXA), basal metabolic rate (BMR) by indirect calorimetry, a questionnaire of nutritional status-Pediatric Nutrition Screening Tool (PNST)-and laboratory parameters were performed. In the cohort of 93 boys aged 8.54 (5.9-12.6 years), inappropriate nutritional status occurred in 41.8% of boys (underweight 11.8%, overweight 16.0%, and obesity 14.0%). In the 10-13 age group, the occurrence of overweight and underweight was the highest. Based on PNST, 15.1% of patients were at nutritional risk (≥2 points)-the most in the 14-17 age group (29%). A negative correlation was identified between PNST and z-scores of body weight, BMI, and FFMI (r Spearman = -0.49, -0.46, and -0.48, respectively; p < 0.05). There were no differences between BMR results from indirect calorimetry and calculations from the Schofield formula for any age group. In obese boys, the caloric requirement in indirect calorimetry was significantly lower than that indicated by the calculations according to the Schofield formula (p < 0.028). Inappropriate nutritional status occurred in almost half of the children with DMD. The age group in which nutritional disorders were most frequently identified was 10-13 years old. PNST could be considered a tool for screening malnutrition after testing a larger group of DMD patients.

Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping.

Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3' UTR harbors a miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mdx52 mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated mdx52 with body-wide miR-146a deletion (146aX). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in 146aX vs. mdx52 muscles while skipped dystrophin transcript levels are unchanged supporting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.

Maintaining Physical Health in Individuals with Duchenne Muscular Dystrophy Through Telerehabilitation.

AIMS: To investigate the effects of a telerehabilitation program on walking performance, lower and upper extremity function, fall frequency, respiratory function, and satisfaction in individuals with Duchenne muscular dystrophy (DMD). METHODS: Thirty children (mean age 8.8 ± 4.2 years) were ambulant (Group 1), and 12 youth (18.5 ± 4.7 years) were non-ambulant (Group 2). The telerehabilitation program was applied by physiotherapists for 24 sessions (3 days/week). The 10-meter walking test, stand up from the supine position test, the modified upper extremity performance test, repetition of Lower and upper extremity movements, and the single breath count (SBC) test were administered. Fall frequency and satisfaction level were also recorded. RESULTS: Significant improvement was found after telerehabilitation in upper extremity performance, repetition of lower and upper extremity movements, fall frequency, and SBC scores in Group 1. Changes in the 10-minute Walk and Stand Up from the Supine Position tests were not significant. There was a significant improvement in SBC scores in Group 2. Satisfaction with the service was 88%. CONCLUSIONS: The 8-week telerehabilitation program was effective in improving aspects of upper and lower extremity function, fall frequency, pulmonary function, and satisfaction levels in individuals with DMD.

Increase in cathepsin K gene expression in Duchenne muscular dystrophy skeletal muscle.

Dystrophinopathy is caused by alterations in the dystrophin gene. The severe phenotype, Duchenne muscular dystrophy (DMD), is caused by a lack of dystrophin in skeletal muscles, resulting in necrosis and regenerating fibers, inflammatory cells, and muscle fibrosis. Progressive muscle weakness is a characteristic finding of this condition. Here, we encountered a rare case of a 10-year-old patient with asymptomatic dystrophinopathy with no dystrophin expression and investigated the reason for the absence of muscle weakness to obtain therapeutic insights for DMD. Using RNA-seq analysis, gene expression in skeletal muscles was compared among patients with asymptomatic dystrophinopathy, three patients with typical DMD, and two patients without dystrophinopathy who were leading normal daily lives. Cathepsin K (CTSK), myosin heavy chain 3 (MYH3), and nodal modulator 3-like genes exhibited a >8-fold change, whereas crystallin mu gene (CRYM) showed a <1/8-fold change in patients with typical DMD compared with their expression in the patient with asymptomatic dystrophinopathy. Additionally, CTSK and MYH3 expression exhibited a >16-fold change (P < 0.01), whereas CRYM expression showed a <1/16-fold change (P < 0.01) in patients with typical DMD compared with their expression in those without dystrophinopathy. CTSK plays an essential role in skeletal muscle loss, fibrosis, and inflammation in response to muscles injected with cardiotoxin, one of the most common reagents that induce muscle injury. Increased CTSK expression is associated with muscle injury or necrosis in patients with DMD. The lack of muscle weakness in the patient with asymptomatic dystrophinopathy might be attributed to the low CTSK expression in the muscles. To the best of our knowledge, this is the first report to demonstrate that CTSK expression was significantly higher in the skeletal muscles of patients with DMD with a typical phenotype than in those without dystrophinopathy.

Respiratory performance in Duchenne muscular dystrophy: Clinical manifestations and lessons from animal models.

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disease. Lack of dystrophin in skeletal muscles leads to intrinsic weakness, injury, subsequent degeneration and fibrosis, decreasing contractile function. Dystropathology eventually presents in all inspiratory and expiratory muscles of breathing, severely curtailing their critical function. In people with DMD, premature death is caused by respiratory or cardiac failure. There is an urgent need to develop therapies that improve quality of life and extend life expectancy in DMD. Surprisingly, there is a dearth of information on respiratory control in animal models of DMD, and respiratory outcome measures are often limited or absent in clinical trials. Characterization of respiratory performance in murine and canine models has revealed extensive remodelling of the diaphragm, the major muscle of inspiration. However, significant compensation by extradiaphragmatic muscles of breathing is evident in early disease, contributing to preservation of peak respiratory system performance. Loss of compensation afforded by accessory muscles in advanced disease is ultimately associated with compromised respiratory performance. A new and potentially more translatable murine model of DMD, the D2.mdx mouse, has recently been developed. Respiratory performance in D2.mdx mice is yet to be characterized fully. However, based on histopathological features, D2.mdx mice might serve as useful preclinical models, facilitating the testing of new therapeutics that rescue respiratory function. This review summarizes the pathophysiological mechanisms associated with DMD both in humans and in animal models, with a focus on breathing. We consider the translational value of each model to human DMD and highlight the urgent need for comprehensive characterization of breathing in representative preclinical models to better inform human trials.

Upregulation of utrophin improves the phenotype of Duchenne muscular dystrophy hiPSC-derived CMs.

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease. Although it leads to muscle weakness, affected individuals predominantly die from cardiomyopathy, which remains uncurable. Accumulating evidence suggests that an overexpression of utrophin may counteract some of the pathophysiological outcomes of DMD. The aim of this study was to investigate the role of utrophin in dystrophin-deficient human cardiomyocytes (CMs) and to test whether an overexpression of utrophin, implemented via the CRISPR-deadCas9-VP64 system, can improve their phenotype. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) lacking either dystrophin (DMD) or both dystrophin and utrophin (DMD KO/UTRN(+/-)). We carried out proteome analysis, which revealed considerable differences in the proteins related to muscle contraction, cell-cell adhesion, and extracellular matrix organization. Furthermore, we evaluated the role of utrophin in maintaining the physiological properties of DMD hiPSC-CMs using atomic force microscopy, patch-clamp, and Ca2+ oscillation analysis. Our results showed higher values of afterhyperpolarization and altered patterns of cytosolic Ca2+ oscillations in DMD; the latter was further disturbed in DMD KO/UTRN(+/-) hiPSC-CMs. Utrophin upregulation improved both parameters. Our findings demonstrate for the first time that utrophin maintains the physiological functions of DMD hiPSC-CMs, and that its upregulation can compensate for the loss of dystrophin.

Sexual health and fertility in Duchenne muscular dystrophy-An exploratory study.

INTRODUCTION/AIMS: Recent clinical guidelines recommend that adolescents with Duchenne muscular dystrophy (DMD) who are on daily glucocorticoid treatment should be offered pubertal induction in order to ensure adult levels of sex hormones as they reach adulthood. However, it remains unclear how gonadal status, including androgen concentrations, impacts physical function and future fertility. The aim of this study was to give a voice to adults with DMD, exploring their perspectives around sexual health, hormone treatment, and fertility. METHODS: Qualitative data was collected from six adults with DMD through two online focus groups. Participants were recruited through Pathfinders Neuromuscular Alliance and Duchenne UK and invited to take part if they had DMD and were 18 years of age or older. Conversations were transcribed verbatim and an interpretivist paradigm was used with thematic analysis. RESULTS: The main themes identified were (1) the need for communication and information about sexual health, (2) dealing with the potential fear of rejection, (3) physical barriers to relationships including sex, (4) testosterone supplementation in DMD, and (5) parenthood and fertility. DISCUSSION: We recommend that clinicians work with young people with DMD individually, to explore the benefits of testosterone treatment for them and their personal sexual health needs. If they are offered treatment, this should always be accompanied by the opportunity for psychological support. This work highlights the need for further research to establish the role of testosterone supplementation in adults with DMD and its effects on fertility and the value of specific emotional and practical support for sexual health.

Essential components of an effective transition from paediatric to adult neurologist care for adolescents with Duchenne muscular dystrophy; a consensus derived using the Delphi methodology in Eastern Europe, Greece and Israel.

PURPOSE: An increasing number of patients with Duchenne muscular dystrophy (DMD) now have access to improved standard of care and disease modifying treatments, which improve the clinical course of DMD and extend life expectancy beyond 30 years of age. A key issue for adolescent DMD patients is the transition from paediatric- to adult-oriented healthcare. Adolescents and adults with DMD have unique but highly complex healthcare needs associated with long-term steroid use, orthopaedic, respiratory, cardiac, psychological, and gastrointestinal problems meaning that a comprehensive transition process is required. A sub-optimal transition into adult care can have disruptive and deleterious consequences for a patient's long-term care. This paper details the results of a consensus amongst clinicians on transitioning adolescent DMD patients from paediatric to adult neurologists that can act as a guide to best practice to ensure patients have continuous comprehensive care at every stage of their journey. METHODS: The consensus was derived using the Delphi methodology. Fifty-three statements were developed by a Steering Group (the authors of this paper) covering seven topics: Define the goals of transition, Preparing the patient, carers/parents and the adult centre, The transition process at the paediatric centre, The multidisciplinary transition summary - Principles, The multidisciplinary transition summary - Content, First visit in the adult centre, Evaluation of transition. The statements were shared with paediatric and adult neurologists across Central Eastern Europe (CEE) as a survey requesting their level of agreement with each statement. RESULTS: Data from 60 responders (54 full responses and six partial responses) were included in the data set analysis. A consensus was agreed across 100% of the statements. CONCLUSIONS: It is hoped that the findings of this survey which sets out agreed best practice statements, and the transfer template documents developed, will be widely used and so facilitate an effective transition from paediatric to adult care for adolescents with DMD.

Is endocrine surveillance important in the care of Duchenne Muscular Dystrophy? Results from a national survey to patients and families on endocrine complications.

Glucocorticoids are standard of care for patients with Duchenne muscular dystrophy (DMD). Although prolonged exposure is associated with multiple endocrine side effects, current guidelines related to monitoring and management of endocrinopathies are suboptimal. We aim to explore community perceptions of endocrine related complications in patients with DMD, assess current level of understanding, and desire for further education. A 31-item online survey was sent through Parent Project to Muscular Dystrophy (PPMD) to Duchenne Registry members to be completed by patients or their caretakers. Response rate was 55% (n = 75). Steroids were taken by 93%, but only 50% were followed by endocrinology and 21% report never been seen by endocrinology. Bone health was discussed with 87% of patients and 60% were diagnosed with osteoporosis. Delayed puberty was discussed with 41% of patients with 23% receiving testosterone therapy. About half the patients reported a diagnosis of slowed growth. Only 51% of the participants recalled discussing adrenal insufficiency. Obesity was discussed with 59% of participants. Families felt education about steroid-induced endocrinopathies to be very or extremely important and prefer to discuss about this at the beginning of their steroid therapy. This demonstrates significant gaps in education and access to endocrine care in patients with DMD.

Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.

Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1 month of voluntary wheel running (WR), 1 month of enforced treadmill running (TR) and 1 month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1 month of age and in situ force production of lower leg muscle was measured at the age of 2 months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.

Characterization of disease-specific alterations in metabolites and effects of mesenchymal stromal cells on dystrophic muscles.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism. Methods: A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mdx mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach. Results and Discussion: We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.

Levels of Exon-Skipping Are Not Artificially Overestimated Because of the Increased Affinity of Tricyclo-DNA-Modified Antisense Oligonucleotides to the Target DMD Exon.

Antisense oligonucleotides (ASO) are very promising drugs for numerous diseases including neuromuscular disorders such as Duchenne muscular dystrophy (DMD). Several ASO drugs have already been approved by the US Food and Drug Administration for DMD and global efforts are still ongoing to improve further their potency, notably by developing new delivery systems or alternative chemistries. In this context, a recent study investigated the potential of different chemically modified ASO to induce exon-skipping in mouse models of DMD. Importantly, the authors reported a strong discrepancy between exon-skipping and protein restoration levels, which was mainly owing to the high affinity of locked nucleic acid (LNA) modifications to the target RNA, thereby interfering with the amplification of the unskipped product and resulting in artificial overamplification of the exon-skipped product. These findings urged us to verify whether a similar phenomenon could occur with tricyclo-DNA (tcDNA)-ASO that also display high-affinity properties to the target RNA. We thus ran a series of control experiments and demonstrate here that exon-skipping levels are not overestimated owing to an interference of tcDNA-ASO with the unskipped product in contrast to what was observed with LNA-containing ASO.

The Dutch Dystrophinopathy Database: A National Registry with Standardized Patient and Clinician Reported Real-World Data1.

Background: Duchenne and Becker muscular dystrophy lack curative treatments. Registers can facilitate therapy development, serving as a platform to study epidemiology, assess clinical trial feasibility, identify eligible candidates, collect real-world data, perform post-market surveillance, and collaborate in (inter)national data-driven initiatives. Objective: In addressing these facets, it's crucial to gather high-quality, interchangeable, and reusable data from a representative population. We introduce the Dutch Dystrophinopathy Database (DDD), a national registry for patients with DMD or BMD, and females with pathogenic DMD variants, outlining its design, governance, and use. Methods: The design of DDD is based on a system-independent information model that ensures interoperable and reusable data adhering to international standards. To maximize enrollment, patients can provide consent online and participation is allowed on different levels with contact details and clinical diagnosis as minimal requirement. Participants can opt-in for yearly online questionnaires on disease milestones and medication and to have clinical data stored from visits to one of the national reference centers. Governance involves a general board, advisory board and database management. Results: On November 1, 2023, 742 participants were enrolled. Self-reported data were provided by 291 Duchenne, 122 Becker and 38 female participants. 96% of the participants visiting reference centers consented to store clinical data. Eligible patients were informed about clinical studies through DDD, and multiple data requests have been approved to use coded clinical data for quality control, epidemiology and natural history studies. Conclusion: The Dutch Dystrophinopathy Database captures long-term patient and high-quality standardized clinician reported healthcare data, supporting trial readiness, post-marketing surveillance, and effective data use using a multicenter design that is scalable to other neuromuscular disorders.

Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is characterized by rapid functional decline. Current available treatment options aim to delay disease progression or stabilize physical function. To aid in healthcare providers' understanding of the symptoms of disease that impact patients' experience, this study explored children's physical functioning, activities of daily living (ADLs), and health-related quality of life (HRQoL) after receiving eteplirsen, a weekly infusion indicated for individuals with DMD with exon 51 skip-amenable mutations. METHODS: Fifteen caregivers of male individuals with DMD participated in a 60-min, semi-structured interview. Open-ended questioning explored changes in the children's condition or maintenance in abilities since eteplirsen initiation. RESULTS: Children with DMD (age 7-15 years [mean 10.9]; steroid treatment at interview, n = 8; time since eteplirsen initiation 3-24 months [mean 14.9]) were described by caregivers as ambulatory (n = 9) and non-ambulatory (n = 6). Caregivers of ambulatory children reported improvements or maintenance of walking ability (n = 7/9), running (n = 6/9), and using stairs (n = 4/9). Continued decline in using stairs was reported by two caregivers. In upper-limb functioning, improvements or maintenances in fine-motor movements were reported by nearly half of all caregivers (n = 7/15), with one caregiver noting a continued decline. Subsequent improvements or maintenances in ADLs were described. Improvements or maintenances in fatigue (n = 9/15), muscle weakness (n = 7/15), and pain (n = 6/15) were reported, although some caregivers described a continued decline (n = 3/15 fatigue, n = 1/15 muscle weakness, n = 2/15 pain). Importantly, most caregivers who reported maintenances in ability perceived this as a positive outcome (n = 6/9). CONCLUSION: This exploratory study indicated that most caregivers perceived improvements or maintenances in aspects of their child's physical functioning, ADLs, and HRQoL since eteplirsen initiation, which they perceived to be a positive outcome.

Duchenne muscular dystrophy (DMD) is a rare disease characterized by progressive muscle weakness. Early on, this weakness presents as difficulty walking, but eventually children lose the ability to walk, develop spinal curvature, and experience problems with the heart and lung muscles. People with DMD are missing a key protein in their bodies called dystrophin. Eteplirsen is a weekly, intravenous treatment approved to treat people with a specific DMD genetic misspelling. The goal of the treatment is to slow down the disease and delay the time to losing ability to walk or needing help breathing. Fifteen caregivers of children living with DMD participated in a 60-min telephone interview. Caregivers were asked questions about the child's DMD symptoms and how those symptoms impact the child's daily life. Caregivers discussed their child's experience while receiving eteplirsen treatment and changes since the start of treatment. Caregivers described their child's muscle weakness and how this has affected their movements (e.g., using stairs, running or walking). Since starting eteplirsen treatment, all caregivers reported some improvement or maintenance in parts of their child's physical functioning, activities of daily living (e.g., sports/leisure, getting dressed and self-care), and symptoms (e.g., muscle weakness, pain and fatigue), even though some decline was also reported (e.g., physical functioning, getting dressed, self-care, muscle weakness, pain and fatigue). The results provide insights into physical functioning and quality of life of children with DMD who are receiving eteplirsen. However, more research is needed to fully understand the impact of eteplirsen on these experiences.

Cardiomyopathy in Duchenne Muscular Dystrophy and the Potential for Mitochondrial Therapeutics to Improve Treatment Response.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene, resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with the development of cardiomyopathy-the leading cause of death-inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD; treatment is aimed at delaying disease progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to the development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial dysfunction is thought to be a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but the effects of such agents on cardiac function remain unclear. The synergistic integration of small molecule- and gene-target-based drugs with metabolic-, immune-, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.

Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report.

BACKGROUND: Zolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before. CASE PRESENTATION: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected. CONCLUSIONS: This study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF.

Acute microtubule changes linked to DMD pathology are insufficient to impair contractile function or enhance contraction-induced injury in healthy muscle.

Duchenne muscular dystrophy (DMD) is marked by the genetic deficiency of the dystrophin protein in striated muscle whose consequence is a cascade of cellular changes that predispose the susceptibility to contraction injury central to DMD pathology. Recent evidence identified the proliferation of microtubules enriched in post-translationally modified tubulin as a consequence of dystrophins absence that increases the passive mechanics of the muscle fiber and the excess mechanotransduction elicited reactive oxygen species and calcium signals that promote contraction injury. Motivated by evidence that acutely normalizing the disease microtubule alterations reduced contraction injury in murine DMD muscle (mdx), here we sought the direct impact of these microtubule alterations independent of dystrophins absence and the multitude of other changes consequent to dystrophic disease. To this end we used acute pharmacologic (epithiolone-D, EpoD; 4 hours) or genetic (vashohibin-2 and small vasohibin binding protein overexpression via AAV9; 2 weeks) strategies to effectively model the proliferation of detyrosination enriched microtubules in the mdx muscle. Quantifying in vivo nerve evoked plantarflexor function we find no alteration in peak torque nor contraction kinetics in WT mice modeling these DMD relevant MT alterations. Quantifying the susceptibility to eccentric contraction injury we show EpoD treatment proffered a small but significant protection from contraction injury while VASH/SVBP had no discernable impact. We conclude that the disease dependent MT alterations act in concert with additional cellular changes to predispose contraction injury in DMD.

Early motor, cognitive, language, behavioural and social emotional development in infants and young boys with Duchenne Muscular Dystrophy- A systematic review.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene. Deficiency of the dystrophin protein causes not only motor, but also cognitive, language, behavioural and social emotional problems. This is the first systematic review investigating five early developmental domains in boys with DMD between 0 and 6 years old. Interactions between different domains and links with mutation types and sites were explored. A systematic search was performed in PubMed, Web of Science and Scopus. An adapted version of the Scottish Intercollegiate Guidelines Network (SIGN) Checklists for case-control and cohort studies was used to evaluate quality. Fifty-five studies of high or acceptable quality were included. One was an RCT of level 1b; 50 were cohort studies of level 2b; and four were an aggregation of case-control and cohort studies receiving levels 2b and 3b. We found that young boys with DMD experienced problems in all five developmental domains, with significant interactions between these. Several studies also showed relationships between mutation sites and outcomes. We conclude that DMD is not only characterised by motor problems but by a more global developmental delay with a large variability between boys. Our results emphasise the need for harmonisation in evaluation and follow-up of young boys with DMD. More high-quality research is needed on the different early developmental domains in young DMD to facilitate early detection of difficulties and identification of associated early intervention strategies.

Probing diffusion of water and metabolites to assess white matter microstructure in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by the absence of functional dystrophin protein. In addition to muscle, dystrophin is expressed in the brain in both neurons and glial cells. Previous studies have shown altered white matter microstructure in patients with DMD using diffusion tensor imaging (DTI). However, DTI measures the diffusion properties of water, a ubiquitous molecule, making it difficult to unravel the underlying pathology. Diffusion-weighted spectroscopy (DWS) is a complementary technique which measures diffusion properties of cell-specific intracellular metabolites. Here we performed both DWS and DTI measurements to disentangle intra- and extracellular contributions to white matter changes in patients with DMD. Scans were conducted in patients with DMD (15.5 ± 4.6 y/o) and age- and sex-matched healthy controls (16.3 ± 3.3 y/o). DWS measurements were obtained in a volume of interest (VOI) positioned in the left parietal white matter. Apparent diffusion coefficients (ADCs) were calculated for total N-acetylaspartate (tNAA), choline compounds (tCho), and total creatine (tCr). The tNAA/tCr and tCho/tCr ratios were calculated from the non-diffusion-weighted spectrum. Mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and fractional anisotropy of water within the VOI were extracted from DTI measurements. DWS and DTI data from patients with DMD (respectively n = 20 and n = 18) and n = 10 healthy controls were included. No differences in metabolite ADC or in concentration ratios were found between patients with DMD and controls. In contrast, water diffusion (MD, t = -2.727, p = 0.011; RD, t = -2.720, p = 0.011; AD, t = -2.715, p = 0.012) within the VOI was significantly higher in patients compared with healthy controls. Taken together, our study illustrates the potential of combining DTI and DWS to gain a better understanding of microstructural changes and their association with disease mechanisms in a clinical setting.