La myopathie cortisonique est une complication fréquente et potentiellement invalidante des traitements prolongés par glucocorticoïdes. Cet article explore en profondeur le contexte historique, l’épidémiologie, la physiopathologie, les manifestations cliniques, les défis diagnostiques et les stratégies thérapeutiques associés à cette condition. Les glucocorticoïdes, bien qu’essentiels dans le traitement de nombreuses maladies inflammatoires et auto-immunes, peuvent induire une faiblesse musculaire progressive et une amyotrophie ciblant particulièrement les fibres musculaires de type II. Les mécanismes physiopathologiques associent une inhibition de la synthèse protéique musculaire (via la voie mTOR/IGF-1) et une activation des systèmes de dégradation (ubiquitine-protéasome et autophagie-lysosome), déclenchés par l’activation des facteurs de transcription FOXO et l’expression de MuRF-1 et de l’Atrogin-1. Le diagnostic combine une évaluation clinique (faiblesse musculaire proximale indolore, atrophie sélective des membres inférieurs), une évaluation électrophysiologique (électroneuromyographie), des examens biologiques (créatine kinase sérique généralement normale ou modérément élevée ; bilan métabolique) et, en cas de doute diagnostique, une analyse histologique (la biopsie musculaire montrant une atrophie préférentielle des fibres de type II, sans infiltration inflammatoire). La prise en charge implique la réduction ou l’arrêt des glucocorticoïdes, la kinésithérapie, et potentiellement des thérapies pharmacologiques ciblées. Des travaux de recherche complémentaires sont néanmoins indispensables pour affiner les outils diagnostiques (biomarqueurs sanguins ou échographiques) et élaborer des stratégies thérapeutiques individualisées, intégrant notamment les profils génétiques (polymorphismes ABCB1 et PAI-1) et métaboliques des patients.

BACKGROUND AND AIMS:Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. METHODS:From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied. RESULTS:Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. CONCLUSIONS:The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.

Background and aims Mutations in myelin protein zero (MPZ) gene are a known cause of Charcot-Marie-Tooth disease. We describe three relatives carrying a likely pathogenic MPZ variant, exhibiting acute or subacute inflammatory-onset demyelinating neuropathies triggered by systemic immune disturbances.Methods We describe a familial case series involving two sisters and one male cousin. The proband (patient A) presented in his 40s with acute-onset demyelinating neuropathy compatible with Guillain-Barré syndrome. In the evolution, he presented three relapses, compatible with chronic inflammatory demyelinating polyneuropathy. He was initially responsive to intravenous immunoglobulin (IVIg) before developing a progressive, treatment-resistant form. Nerve biopsy was compatible with hereditary neuropathy. His cousin, in her 50s (patient B), was diagnosed with anti-myelin associated glycoprotein neuropathy. Immunosuppressive treatment is ongoing, with objective clinical response. Her sister (patient C) developed in her 50s a dysautonomia-predominant demyelinating neuropathy after COVID-19 infection, requiring cardiac defibrillator implantation. No immunomodulatory treatment was necessary in her case. All three harboured the heterozygous c.448G>T (p.Val150Leu) MPZ variant.Results Comprehensive investigations including blood work, nerve conduction studies, cerebrospinal fluid analysis and genetic testing confirmed a shared likely pathogenic c.448G>T (p.Val150Leu) MPZ variant. The temporal relationship between symptom onset and systemic immune stressors was consistent across cases.Discussion We propose that MPZ-related neuropathy may exhibit heightened vulnerability to inflammatory triggers. This predisposition could reflect disrupted protein homeostasis within Schwann cells, linking endoplasmic reticulum stress and immune activation. Further studies are needed to explore mechanisms of immune susceptibility in hereditary neuropathies.

ObjectivesTo evaluate the effectiveness and safety of zilucoplan in the real-world treatment setting in France.MethodsThis retrospective cohort study evaluated patients with generalized anti-AChR myasthenia gravis (MG) failing current therapy enrolled in the French early access program (EAP) for zilucoplan. Patients were evaluated at enrollment and at Months 1, 3 and 6 with the MG-ADL score, the Myasthenic Muscle Score (MMS-Garches), and the MG-quality of life questionnaire (MG-QoL15r). MG crises and on-treatment adverse events were documented. MG medication use was compared between the six months before and after enrollment.ResultsForty-eight patients were enrolled and treated with zilucoplan (mean age: 56.2 years; 50.9% men). Thirty patients achieved six months follow-up before the EAP ended. Three patients discontinued zilucoplan due to lack of efficacy. Mean MG-ADL score decreased from 7.4 ± 4.4 to M0 to 2.5 ± 2.7 at M6 (p < 0.0001). 9/43 patients achieved minimal symptom expression at M3 and 12/30 at M6. Mean MMS-Garches score was 67.5 ± 20.0 at M0 and 87.5 ± 13.2 at M6 (p < 0.0001). Mean MG-QoL15r score was 18.2 ± 8.6 at M0 and 8.7 ± 8.3 at M6 (p = 0.0156). 15 patients experienced adverse events, leading to discontinuation in four cases. The mean oral corticosteroid dose decreased from 28.8 ± 11.8 mg to 17.9 ± 11.8 (p = 0.001). Six patients experienced MG crises on treatment, compared to 22 in the six months preceding enrollment. treatment.DiscussionFollowing initiation of zilucoplan treatment, we observed an improvement in MG symptoms and a reduction in MG crises and in exposure to oral corticosteroids. Overall, zilucoplan was well-tolerated with no major adverse events reported.Trial registration informationThe study was registered in the clinicaltrials.gov trial registry under the number NCT06815133 (https://clinicaltrials.gov/study/NCT06815133) on February 4th, 2025.

Glucocorticoid-induced myopathy is a frequent and potentially disabling complication of prolonged glucocorticoid therapy. This article provides an in-depth exploration of the historical context, epidemiology, pathophysiology, clinical manifestations, diagnostic challenges, and therapeutic strategies associated with this condition. While glucocorticoids are essential in treating numerous inflammatory and autoimmune diseases, they can induce progressive muscle weakness and atrophy, particularly affecting type II muscle fibers. The pathophysiological mechanisms involve inhibition of muscle protein synthesis (via the mTOR/IGF-1 pathway) and activation of protein degradation systems (ubiquitin-proteasome and autophagy-lysosome pathways), triggered by the activation of FOXO transcription factors and the upregulation of atrogenes (MuRF-1 and Atrogin-1). Diagnosis relies on a comprehensive clinical assessment (proximal muscle weakness without pain, selective atrophy of the lower limbs), laboratory investigations (serum creatine kinase levels typically normal or mildly elevated; metabolic panel), electrophysiological study (electroneuromyography), and, in cases of uncertain diagnostic, histological analysis (muscle biopsy revealing preferential atrophy of type II fibers, without inflammatory infiltration). Management strategies include gradual reduction or discontinuation of glucocorticoids, physical rehabilitation (resistance and endurance exercises), and targeted pharmacological therapies. Further research is essential to refine diagnostic tools (e.g., blood or ultrasound biomarkers) and develop personalized therapeutic approaches, incorporating genetic (e.g., ABCB1 and PAI-1 polymorphisms) and metabolic patient profiles.

BACKGROUND:Clinical guidelines for treating myasthenia gravis (MG) recommend avoiding certain therapies because of a risk of exacerbating MG. We evaluated use of statins and other classically contraindicated therapies and their impact on healthcare outcomes among patients with MG in France. METHODS:This was an observational, retrospective, longitudinal cohort study using data from the French national health insurance database. Adult patients with MG-related claims from 2013 to 2020 were included. The first MG claim date was the index date, with follow-up until end-of-study or death. Multivariable regression models evaluated the risk of intensive care unit (ICU) admission for MG or death during periods of exposure versus nonexposure to contraindicated treatments. RESULTS:Of 14,459 individuals with MG, 12,954 (89.6%) received a contraindicated treatment during follow-up, and 4160 (28.8%) received statins. In multivariable regression analyses, exposure to any contraindicated treatment was not significantly associated with risk of ICU admission for MG (hazard ratio [HR] 1.038; 95% confidence interval [CI] 0.968-1.113; p = not significant) but was associated with significantly higher risk of death (HR 1.167; 95% CI 1.075-1.266; p < 0.001) versus nonexposure. In contrast, statins were associated with a greater risk of ICU admission (HR 1.133; 95% CI 1.065-1.205; p < 0.001) but lower risk of death (HR 0.626; 95% CI 0.565-0.694; p < 0.001). CONCLUSION:This large, real-world study suggests that for some contraindicated medications, including statins, longer-term mortality benefits are likely to outweigh short-term risks of exacerbating MG.

BACKGROUND:The French National Rare Diseases Registry (BNDMR) was established in 2007 to ensure access to optimal care standards for all patients with rare diseases in dedicated reference centres. The objective of this retrospective cohort study was to describe patients with myasthenia gravis (MG) in the BNDMR. METHODS:All patients aged ≥ 18 years in the BNDMR with a confirmed diagnosis of MG visiting a reference centre at least once between 2007 and 2021 (inclusive) were included. Diagnosis was defined through ORPHA:589 or ORPHA:391490 disease codes. Patients were followed for ≥ 12 months until 31 December 2022 (or until death). Data were collected on demographics and disease history. Mortality was estimated using Kaplan-Meier survival analysis. Healthcare resource utilisation at the reference centre was documented. RESULTS:Overall, 3963 patients were analysed. Mean follow-up duration was 6.1 ± 3.8 years. The median interval between diagnosis and inclusion was 3.8 months [IQR: 1.5-7.5] and the median age at symptom onset was 52.0 [IQR: 34.0-69.0] years. Survival probability was 82.7% at 10 years, and higher in women than men (p < 0.001; logrank test). The mean interval between visits was 4.1 months. The mean number of overnight or day hospitalisations per patient was 2.6 ± 3.4 and the mean number of physician consultations per patient per year was 1.7 ± 1.1. CONCLUSION:This national registry study provides reference data for patients in France with a confirmed diagnosis of MG. However, all patients with MG are still not managed in dedicated reference centres.

BACKGROUND:Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterized by progressive muscle weakness and atrophy. In adult patients, treatment goals are to stabilize the disease or gain motor skills. However, functional scales commonly used to assess treatment response, such as the 32-item Motor Function Scale (MFM32) are less sensitive in severely affected adult patients due to floor effect. The study's objective was to evaluate personalised patient reported outcome (PRO), centred on patient expectations, that combines two patient-centred tools widely used in occupational therapy: the Canadian Occupational Performance Measure (COPM) and Global Attainment Scale (GAS). METHODS:A multicenter, retrospective cohort study of patients treated for SMA was conducted. Collected data included patients' characteristics, treatments received, and outcome evaluations with MFM32, COPM and GAS. RESULTS:Thirty-two patients with type 1, 2, or 3 SMA were included. At treatment initiation, mean MFM32 total score was 37.1 ± 24.3. COPM identified patient's expectations were primarily centred on the domain of mobility and self-care. After a mean treatment duration of 14.1 ± 4.3 months, a clinically significant improvement was reported for five (15.6%) patients with MFM32. Eleven (34.4%) patients showed improvement on performance and 10 (31.2%) on satisfaction score in their most significant patient-identified problem areas in daily function as assessed by the COPM. Twenty (62.5%) patients achieved at least one of their therapeutic goals measured with the GAS. A positive correlation was found between change in satisfaction score and GAS (r = 0.521, p = 0.003). CONCLUSION:The combined COPM/GAS approach is a personalised fit-for-purpose instrument able to detect improvements, meaningfully significant to the patient, which are not always captured by usual functional scales.

Titinopathies are complex neuromuscular disorders with multiple phenotypes. The gene's size, comprising 364 exons, as well as the protein's size of 3.8 MDa and its extensive network of protein interactors, are key factors underlying this complexity. Various phenotypes characterize titinopathies, and this study focuses on two of them: arthrogryposis and myofibrillar myopathies. The protein deregulations associated with these two phenotypes remain unknown or have been minimally explored; however, understanding these consequences is essential for better characterizing the pathophysiological aspects of these titinopathies.The objective was to analyze protein deregulations in two cohorts of French patients with titinopathies exhibiting the arthrogryposis and myofibrillar myopathy phenotypes, and to compare them with control individuals. Protein extracts were obtained from muscle biopsies of patients, and changes in protein levels within these two groups were analyzed by mass spectrometry. The results indicate specific deregulations in each group. The networks analyzed revealed deregulation of proteins involved in fibrosis mechanisms or in the actomyosin complex for the arthrogryposis phenotype. Regulation of the muscle contraction system through deregulation of proteins involved in the cytoskeleton is impacted in patients with myofibrillar myopathy. The proteins that are quantitatively abnormal in these two groups also provide insights into the major signaling networks disrupted in titinopathies. These findings will contribute to a more precise characterization of titinopathies, enabling the identification of phenotype-specific biomarkers and potentially guiding the search for targeted therapies for these neuromuscular disorders.

Calpainopathies, including limb-girdle muscular dystrophy recessive type 1 (LGMD R1) and the rare dominant type 4 (LGMD D4), are genetic neuromuscular disorders caused by pathogenic variants in the CAPN3 gene, which encodes calpain-3, a muscle-specific cysteine protease. This protein plays a crucial role in muscle remodelling, calcium homeostasis, and myogenesis regulation. LGMD R1, the most common form of LGMD, is characterized by progressive, symmetrical muscle weakness primarily affecting the shoulder and pelvic girdles, with an onset ranging from childhood to adulthood. It affects about 1 in 100,000 individuals. The clinical spectrum is wide, with three main phenotypes: pelvifemoral myopathy, scapulohumeral myopathy, and isolated hyperCKemia. LGMD D4 is characterized generally by a milder phenotype with variable but frequent axial muscle involvement. Diagnostic algorithm include serum CK levels dosage, muscle imaging, and sometimes a muscle biopsy, with definitive diagnosis confirmed by CAPN3 gene testing. Calpainopathies have no cure and care is focused on physiotherapy, management of muscle contractures, moderate physical activity, and orthosis. The newly established French National Diagnosis and Care Protocol (NDCP) aim to standardize the diagnosis and care of calpainopathies. The protocol emphasizes early diagnosis, personalized patient care, genetic assessment and prevention of disease progression. This initiative aims to reduce diagnostic delays and improve patient outcomes through a harmonized multidisciplinary approach, informed by the latest clinical and research expertise.

Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients not given antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-α2 and IFN-ω in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, neutralizing both IFN-α2 and IFN-ω in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng/mL of both IFN-α2 and IFN-ω (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1 to 78.9], P = 0.0010) or IFN-α2 at any dose (OR [95% CI]: 4.7 [1.5 to 15.0], P = 0.0054) than in those without such autoantibodies. The risk of producing AAN-I-IFN was much higher in MG patients than in the general population (OR [95% CI]: 28.9 [10.8 to 77.7], P = 4.9 × 10-27). Thymoma was found in 14 patients and increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6 to 19.4], P = 0.0050) and hypoxemic pneumonia (9.2 [1.9 to 44.2]; P = 0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, which are, in turn, associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.

INTRODUCTION/AIMS:Rozanolixizumab, an inhibitor of the neonatal Fc receptor (FcRn), is used to treat patients with generalized myasthenia gravis (gMG) refractory to standard therapies. However, the approved six-week cyclic regimen may be associated with a "wearing-off" effect and disease fluctuations. We evaluated the non-cyclic administration of rozanolixizumab in patients with complex gMG. METHODS:We retrospectively studied eight patients with anti-acetylcholine receptor antibody-positive complex gMG treated at Bordeaux University Hospital. "Complex" was defined by refractoriness, contraindications, intolerance to immunosuppressants or highly active MG. Patients transitioned to weekly or fortnightly rozanolixizumab after relapse during intermittent therapy. The primary outcome was ≥ 2-point improvement in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at 3 months. Clinical data and serum immunoglobulin G (IgG) levels were collected at baseline, 3, 6, and 12 months. RESULTS:The cohort (mean age 70.5 years; 75% female) had a mean baseline MG-ADL score of 10.8, which improved rapidly to 4.1 at 3 months. Hospitalization days dropped from 15.8/month pre-treatment to zero by 6-12 months. Corticosteroids were tapered from 30.3 to 13.3 mg/day at 1 year. Mean serum IgG levels declined by almost 50% and stabilized. Only one discontinuation occurred due to gastrointestinal symptoms; no serious infections or severe adverse events were observed. DISCUSSION:Fortnightly rozanolixizumab yielded sustained clinical benefits, reduced hospitalizations, and enabled steroid tapering in complex gMG patients. This approach may prevent cyclical relapses seen with intermittent dosing. Larger studies are needed to confirm efficacy and long-term safety.

Glucocorticoid-induced myopathy (GIM) is a prevalent and often underdiagnosed condition that significantly impacts the quality of life and functional capabilities of affected individuals. This review summarises the current understanding of GIM, focussing on its pathophysiology, diagnostic challenges, and emerging therapeutic strategies. A comprehensive review of the literature was conducted to identify relevant studies on GIM. Databases, such as PubMed, Embase, and Web of Science, were searched using keywords related to GIM, pathophysiology, diagnosis, and treatment. Studies were selected based on their relevance to the topic and the quality of their methodologies. GIM is characterised by proximal muscle weakness, atrophy, persistent fatigue, and reduced muscular endurance, predominantly affecting the lower limbs. The pathophysiology involves both catabolic and anti-anabolic mechanisms, leading to the degradation of muscle proteins and inhibiting protein synthesis. Diagnostic challenges include the nonspecific nature of symptoms and the lack of sensitive biomarkers. Emerging therapeutic strategies include the use of growth hormones, insulin-like growth factor-1, branched-chain amino acids, and creatine although their efficacy in humans requires further validation. Physical therapy, particularly resistance and aerobic exercise, has shown promise in managing GIM. The diagnosis and management of GIM require a multifaceted approach, including early diagnosis, optimised corticosteroid use, and targeted therapies. Future research should focus on developing improved biomarkers for early detection, exploring genetic susceptibility, and validating the efficacy of emerging therapeutic interventions to improve outcomes for patients with GIM.

This retrospective study identified 125 audio-visual works from cinema and television, including films, TV series, and documentaries, depicting neuromuscular disorders since 1910. Motor neuron disorders, including amyotrophic lateral sclerosis (ALS), had the highest representation (69.3%), followed by myopathies (20%). The predominant genre was documentary (48%), which offered more factual representation than fictional works. ALS was overrepresented due to its dramatic nature and association with notable figures, including the American baseball player Lou Gehrig and British theoretical physicist Stephen Hawking; other neuromuscular disorders, such as Duchenne muscular dystrophy, were depicted less frequently. Despite inaccuracies in some portrayals, these works raise public awareness and contribute to a greater understanding of rare diseases, such as neuromuscular disorders, among the general public.

Background Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which encodes dystrophin in skeletal muscle cells. Although the role of dystrophin as a structural protein is well known, the cellular processes underlying myofiber degeneration are still not fully understood. Despite advances from studies in murine models, these models do not fully replicate the human pathology. Methods We investigated sarcolemmal integrity, membrane repair capacity, and annexin protein expression in DMD patient muscle biopsies and human skeletal muscle cell lines using immunohistochemistry, a shear stress-based injury assay, western blotting, and live-cell imaging of GFP-tagged annexins. Results We identified defective membrane repair in DMD skeletal muscle cells, independent of increased membrane fragility. Massive intracellular IgG uptake and impaired resealing after mechanical stress, respectively observed ex vivo and in vitro, confirmed this defect. We also observed altered expression patterns of annexins, a family of key proteins involved in membrane repair. Control skeletal muscle cells upregulate ANXA5 and ANXA6 upon mechanical stress, likely as part of an adaptive mechanism to counteract membrane damage. Conversely, DMD cells failed to induce this upregulation. Strikingly, ANXA2 was not only significantly overexpressed in DMD cells but also aberrantly localized to the extracellular space due to the defect in membrane repair. This extracellular ANXA2 is associated with adipocyte accumulation in muscle tissue, suggesting a mechanism similar to that seen in dysferlinopathies. Conclusions Our findings propose that ANXA2 contributes to muscle degeneration in DMD and highlight it as a potential therapeutic target to prevent adipogenesis and muscle loss. ### Competing Interest Statement The authors have declared no competing interest. * ANXA2 : Annexin-A2 DMD : Duchenne muscular dystrophy FAP : fibro-adipogenic progenitors IgG : immunoglobulin type G MD : muscular dystrophies PI : propidium iodide AFM-telethon, grant 22442, grant 24991, grant 23881

BACKGROUND AND OBJECTIVES:Mortality in Late-Onset Pompe Disease (LOPD) has been associated with the rapid progression of respiratory and motor impairment. However, an in-depth approach to the exact causes of death in these patients is still lacking. METHODS:In this retrospective cohort study, we analyzed the cause of death and the comorbidities of all deceased patients from the French Late-Onset Pompe Disease registry. RESULTS:By the time of the last extraction, 60 patients diagnosed with LOPD and monitored were registered as deceased in the French national registry, out of a total of 260 patients included. The median age of death was 70.5 years, while the median age of diagnosis was 58 years. The causes of death were divided into disease-related, accounting for 46.6% of deaths, and non-disease-related, comprising 28.3% of total deaths. Fifteen patients (25%) died of an unknown cause. The most frequent etiology of disease-related death was respiratory failure (n = 14), while for the non-disease-related group, malignant neoplasm was the most common (n = 8). Patients in the non-disease-related death group had significantly higher forced vital capacity (FVC) values compared to those in the disease-related death group (54.7% vs. 38%). Treatment-wise, the median period elapsed from diagnosis to ERT introduction was higher in the disease-related group. DISCUSSION:This is the first study to focus on the specific causes of death of LOPD patients. The majority of the LOPD deaths in the French registry were attributed to respiratory failure and malignant neoplasms.