BACKGROUND:Facioscapulohumeral dystrophy (FSHD) and Myasthenia Gravis (MG) are well-known rare neuromuscular diseases of respectively genetic and acquired origin. Among muscular dystrophies, the co-occurrence of MG with FSHD is the most common, representing a non-negligible "double trouble". Here, we aim to describe a series of patients with coexistence of these two rare disorders and combine this with a review of the literature to identify common elements which might provide useful clues when evaluating a FSHD patient with uncommon clinical presentation compatible with MG. METHODS:We retrospectively collected demographic, clinical, and laboratory data of patients affected by both FSHD and MG followed at the Nice University Center, and we performed a review of the literature. RESULTS:We identified 10 patients in our cohort, 7 females. All patients have a D4Z4 4qA allele of 7-10 RU, a disease onset > 45 years and a mean FSHD score of 9.6 ± 2 at the last evaluation. The mean age of onset of MG was 68.5 ± 7.6 years; all patients presented with anti-AChR antibodies and without thymic pathology, and MG appeared in all but two patients after FSHD. We identified 9 case reports in the literature. All of them presented with AChR positivity. The majority of them presented with a late and very late onset MG and without thymic pathology. CONCLUSIONS:Our results underline the need for careful clinical evaluation to identify uncommon features, especially in elderly FSHD patients carrying a D4Z4 4qA allele of 7-10 RU to exclude the coexistence of other treatable neuromuscular conditions.

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.

Background: There is a considerable challenge in managing non-dystrophic myotonias (NDM), due to the lack of gold-standard outcome measures to assess NDM burden on activities of daily living and quality of life from the patient's perspective. Objective: In this study, we aim to develop and validate a specific NDM patient-reported outcome (PRO) questionnaire. Methods: The Active-NDM questionnaire was developed through a modified 2-round Delphi procedure integrating feedback from stakeholders and a systematic literature review, with input from 11 national clinical experts. The questionnaire was validated in a pilot study of 10 patients with NDM. Both clinical experts and patients assessed questions for pertinence/relevance and clarity. We excluded questions that were not considered pertinent/relevant, and reformulated any judged to be poorly formulated, by >80% of the experts/patients. We also excluded questions with <80% reproducibility during the pilot study. Results: Based on feedback from experts and findings of the systematic literature review, we identified 130 questions, of which 100 were unduplicated. During the Delphi process, we removed 66 questions due to lack of pertinence and/or relevance. In the pilot study, patients with NDM evaluated the resulting 34-questions for pertinence, clarity, and reproducibility. Subsequently we removed 9 questions that did not achieve the required level of reproducibility. Conclusion: We developed the Active-NDM questionnaire, composed by 25 questions, figuring as a new NDM-specific measure to determine the impact of the disease on patients' activities of daily living and quality of life. Active-NDM could be a valuable tool in the management of patients with NDM. These findings should be interpreted as preliminary. Larger-scale validation studies are warranted to confirm the tool's psychometric properties and generalizability. ClinicalTrials.gov identifier: NCT06136416

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.

BACKGROUND:Losmapimod is an orally administered small molecule and selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor able to reduce aberrant expression of DUX4 in vitro and thereby potentially slowing disease progression in patients with facioscapulohumeral muscular dystrophy (FSHD). OBJECTIVE:This global, randomized, placebo-controlled, double-blind phase 3 study in patients with FSHD1 and FSHD2 examined the efficacy and safety of losmapimod over a 48-week treatment period compared to placebo (NCT05397470, EUDRACT 2022-000389-16). METHODS:The primary endpoint was change in quantification of reachable workspace (RWS) expressed as relative surface area (RSA). Other endpoints included measures of muscle composition (fat content and lean muscle) using magnetic resonance imaging (MRI), muscle strength using quantitative dynamometry, and quality of life measures. RESULTS:130 participants received losmapimod and 130 participants received placebo, with 252 participants completing the 48-week treatment period. There were no statistically significant differences between groups in change in RSA and all secondary efficacy endpoints from baseline to Week 48. Losmapimod treatment was well-tolerated, and most adverse events were mild. CONCLUSIONS:Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies.

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder characterized by marked clinical and molecular heterogeneity. Over more than two decades, molecular diagnosis has relied on Southern blotting to resolve the complex D4Z4 macrosatellite at chromosome 4q35. While this approach remains a reference standard, its technical constraints and the need for complementary layers of information have become more evident as FSHD diagnostics is increasingly required to support patient stratification, genotype-phenotype correlation, and clinical trial readiness. In this context, the review traces the evolution of FSHD diagnostics from classical molecular approaches to modern genome-scale technologies that enable direct characterization of the D4Z4 locus, improve interpretation of borderline and atypical cases, and support integrated diagnostic workflows. Beyond technical innovation, the review highlights the growing need for harmonized diagnostic algorithms, international collaboration, and federated data infrastructures to support consistent interpretation across populations and healthcare systems. It further emphasizes how emerging requirements for molecular stratification in clinical trials, together with persistent global disparities in access to genetic testing, are reshaping priorities in FSHD diagnostics, positioning FSHD as a model for how rare disease diagnostics can integrate classical expertise with next-generation technologies to support clinical care, trial readiness, and more equitable access to diagnosis worldwide.

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.

Introduction La réalité virtuelle (RV) est une distraction immersive et multisensorielle efficace pour réduire douleur et anxiété dans divers contextes cliniques. Son utilisation lors d’injections intrathécales (IT) reste inexplorée. Objectifs Évaluer l’efficacité de la RV en sus des soins courants (SoC) pour atténuer l’anxiété lors d’injections IT de nusinersen chez des patients atteints de SMA et l’expérience RV des patients/soignants. Méthodes REALITY (NCT05354414) est un essai prospectif, randomisé, croisé, ouvert, mené dans 15 centres français. Des patients≥7 ans recevant des injections IT de nusinersen tous les 4 mois (doses de maintien) étaient randomisés 1:1 pour recevoir lors de leurs prochaines injections IT1/IT2, RV+SoC puis SoC ou inversement. Les critères d’évaluation incluaient : auto-évaluation de l’anxiété et de la douleur, usage d’antalgiques/anxiolytiques, satisfaction et acceptabilité rapportées par les patients et les équipes médicales. Résultats Au total, 59 patients (âge médian 19,7 ans ; SMA II, 40,7 % ; III, 54,2 %) ont eu≥1IT. Aucune réduction significative de douleur, d’anxiété ou de consommation médicamenteuse n’était observée entre RV+SoC vs SoC, bien que les besoins en distractions supplémentaires aient été moindres avec la RV (15,2 % vs 30,9 %). La satisfaction était élevée chez les patients et les soignants. Quatre événements indésirables non graves liés à la RV ont été rapportés. Discussion En France, le SoC assure déjà une prise en charge efficace de l’anxiété, pouvant limiter la détection d’un bénéfice additionnel de la RV. Des études supplémentaires seraient nécessaires pour explorer le moment optimal d’utilisation de la VR (avant vs pendant l’injection IT) et identifier les sous-groupes les plus susceptibles d’en bénéficier. Conclusion La RV associée aux soins courants lors des injections IT semble bien acceptée par patients et soignants, même sans réduction significative de la douleur ou l’anxiété comparée au SoC seul.

The broad clinical and genetic heterogeneity of mitochondrial diseases makes diagnosis challenging. Accurate characterization of novel variants is crucial to reduce diagnostic uncertainty, guide treatment, and enable reliable genetic counseling. In this study, we validated a single-cell NGS-based analysis approach by comparison with conventional PCR-RFLP and applied it to five mtDNA variants identified in patients evaluated at our national reference center for mitochondrial disorders (CALISSON). Variant interpretation was assessed using multiple frameworks, including Yarham's scoring, Wong's specifications, and the ClinGen guidelines. We report four novel variants (m.9998 T > C in MT-TG, m.7530A > G in MT-TD, and m.4271G > C and m.4305A > G in MT-TI), including three for which single-fiber analysis provided strong evidence supporting pathogenicity. However, these functional results alone were not sufficient to enable reclassification under the current ClinGen framework. These findings highlight differences between the various scoring systems and illustrate the limitations of current recommendations in fully integrating functional evidence and tissue segregation data. We therefore suggest that adjusted weighting of existing criteria may improve variant classification. Nevertheless, classification frameworks must preserve reproducibility across laboratories, and the criteria proposed here should be considered preliminary points for reflection requiring further validation in larger cohorts, as well as the establishment of standardized criteria for functional studies, including single-fiber analyses.

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) shows marked clinical heterogeneity, partly related to age at onset. We analysed baseline, 12- and 24-month follow-up data from 231 FSHD1 patients enrolled in the ReSolve study (NCT03458832) to compare clinical, genetic, and epidemiological features between adult-onset (n = 190) and late-onset (n = 41) patients. Differences were assessed using generalized linear models and repeated-measures covariance analyses adjusting for demographics and disease duration. Late-onset patients were predominantly female (58.5%, p = 0.039), older (64.8 ± 6.3 vs 47.6 ± 13.5 years; p < 0.001), and carried longer D4Z4 repeats (6.5 ± 1.6 vs 5.7 ± 1.8; p = 0.01). They showed milder facial and upper limb involvement but greater lower limb impairment, evaluated with TUG (2.37 vs 2.11 s, p = 0.001) and 6MWT (329.16 vs 415.22 meters, p = 0.002), despite shorter disease duration. Lower limb weakness was the most frequent initial symptom (30% vs 10.7%, p = 0.0029). After one year, late-onset patients maintained similar characteristics, while facial differences were no longer significant at two years. Disease progression was similar across outcome measures except for the FSHD clinical score, which worsened more in late-onset patients at two years. These findings indicate that late-onset FSHD1 represents a distinct clinical phenotype relevant for outcome measure selection and personalized management strategies.

BACKGROUND AND OBJECTIVES:Goals for comprehensive care are important in the management of individualized treatment for patients with myasthenia gravis (MG), a disease with variable presentation and degrees of severity. Yet there is limited guidance on how comprehensive care should be achieved and implemented. We present global consensus recommendations for comprehensive care of patients with MG. METHODS:An international panel of experts was formed, and a targeted literature review was conducted to inform the recommendations. A steering committee selected relevant topics and draft recommendations were developed for each topic. Formal consensus was achieved using the RAND/UCLA appropriateness method. Seventeen panelists from North America, Europe, and Asia rated statements online from 1 ("extremely inappropriate") to 9 ("extremely appropriate") and provided comments and suggestions for modifications. The methodologist modified statements for further rating, based on panel scores and feedback. Statements achieving agreement as appropriate by 4 rounds of rating were accepted. RESULTS:Consensus was achieved for 21 statements. Statement 1 defined the ongoing treatment goal: "to work toward, achieve, and sustain minimal symptoms and treatment-related adverse events, with a patient-acceptable quality of life (using validated measures)". Subsequent statements described implementation of this goal and covered: early control of symptoms; establishing and sustaining a treatment goal; vaccination and screening for infection; family planning/pregnancy; management of fatigue and comorbidities; and management of impending crisis and crisis. DISCUSSION:Expert consensus was achieved on a series of global recommendations for comprehensive care goals, which has implications for improved disease outcomes and health-related quality of life for patients with MG. These recommendations will require updating as treatment paradigms evolve.

Nerve ultrasound (n-US) supports the diagnosis of multifocal motor neuropathy (MMN), though most studies focus on nerve enlargement (NE) and its distribution. This study explored nerve echotexture using ultrahigh-frequency ultrasound (UH-FUS) in 13 MMN patients (mean age 61.9 years, disease duration 147 ± 105 months). NE was detected in 77%, preferentially involving median nerve, yet conduction blocks corresponded to NE in only 15%. Notably, 92% showed mixed/hyperechoic echotexture, including three patients with normal CSA, suggesting microstructural remodeling beyond swelling. No hypoechoic nerves were observed, consistent with limited acute inflammation. Combining echogenicity with NE assessment may improve n-US sensitivity, especially in atypical MMN.

Late-onset Pompe disease (LOPD) is caused by α-glucosidase (GAA) deficiency, leading to glycogen accumulation resulting in progressive muscular weakness and respiratory insufficiency. Glycogen overload, vacuolation, and autophagic accumulation are the histological hallmarks of the disease. However, markers capable of tracking the progression of LOPD across different disease stages remain insufficiently characterized. We performed a comprehensive myopathologic analysis of eleven LOPD muscle biopsies from untreated patients (age range 7-69 years) and compared them to eleven biopsies from histologically normal age-matched controls. The cohort was divided into two groups considering the age at muscle biopsy below or above 33 years: (1) younger LOPD and (2) older LOPD, respectively. We quantified periodic acid-Schiff-positive fibers, vacuolated fibers using a novel vacuolation severity score, autophagic markers, and satellite cell behavior. We observed prominent vacuolization, glycogen overload, and autophagic bodies in younger LOPD. Moreover, this group showed higher regenerative features accompanied by an increase in the percentages of active satellite cells compared to older LOPD. In conclusion, autophagy impairment correlates with enhanced satellite cell activation in muscle biopsies from younger LOPD patients. These findings suggest that stimulating satellite cell activity may hold therapeutic potential for addressing LOPD progression in its early stages.

Background and ObjectivesTwinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders.MethodsA retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns.ResultsThe study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions.DiscussionThis large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.

Late-onset Pompe disease (LOPD) is a progressive myopathy. Enzyme replacement therapy is effective, but long-term outcomes vary. Avalglucosidase alfa, shown to be non-inferior to alglucosidase alfa in a phase 3 trial, became available in France through compassionate use for patients with insufficient response to alglucosidase alfa. METHODS:Data from the French Pompe registry were analyzed for patients who switched to avalglucosidase alfa with at least 1 year of follow-up. Respiratory function (forced vital capacity, FVC) and motor function evaluated with gait performance (Six-Minute Walk Test, 6MWT) were assessed before the switch, and one and 2 years after. Individual changes were compared using paired-sample tests. RESULTS:Forty-seven adult patients were included. A stabilization of motor decline was observed: prior to switching, the 6MWT decreased by -27 m/year, whereas an improvement of +17 m/year was seen during the first year after the switch (p = 0.001), followed by overall stability in the second year (-10 m/year, p = 0.280). Respiratory changes were not statistically significant: a decline of 60 mL/year before the switch versus 10 mL/year after 1 year (p = 0.161), and 20 mL/year during the second year (p = 0.346). Three patients died during follow-up, with causes unrelated to the disease or treatment. DISCUSSION:Gait deterioration halted during the first year after transitioning to avalglucosidase, with sustained stabilization thereafter, while respiratory parameters showed minimal change. For patients experiencing significant walking decline under alglucosidase alfa therapy, switching to avalglucosidase alfa resulted in disease stabilization, beginning with mild improvement in the first year and a return to pre-switch baseline thereafter.

BACKGROUND AND OBJECTIVES:Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders. METHODS:A retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns. RESULTS:The study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions. DISCUSSION:This large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.