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X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0–30·9; range 9·5–49·7) in the lower dose cohort, 31·1 months (16·0–64·7; 6·8–72·7) in the higher dose cohort, and 18·7 months (10·1–31·5; 5·9–39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0–49·5; range 2·1–54·7) for lower dose participants, 27·6 months (24·6–29·1; 3·4–41·0) for higher dose participants, and 28·3 months (9·7–46·9; 5·7–32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. Astellas Gene Therapies.

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

Background Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. Methods To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. Results Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical–histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. Conclusions Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.

PurposeIndividuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM.DesignRECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care.ResultsOutcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7–5.6) vs 30.2 years (IQR 19.4–30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7–30.2) vs 1.8 years (IQR 0.2–not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1–not estimable) vs 0.2 years (IQR 0.1–2.1)).ConclusionsHigh mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies.Trial registration number NCT02231697

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy. Most (80%) children with XLMTM have profound muscle weakness and hypotonia at birth resulting in severe respiratory insufficiency, the inability to sit up, stand or walk, and early mortality. At birth, 85–90% of children with XLMTM require mechanical ventilation, with more than half requiring invasive ventilator support. Historically, ventilator-dependent children with neuromuscular-derived respiratory failure of this degree and nature, static or progressive, are not expected to achieve complete independence from mechanical ventilator support. In the ASPIRO clinical trial (NCT03199469), participants receiving a single intravenous dose of an investigational gene therapy (resamirigene bilparvovec) started showing significant improvements in daily hours of ventilation support compared with controls by 24 weeks post-dosing, and 16 of 24 dosed participants achieved ventilator independence between 14 and 97 weeks after dosing. At the time, there was no precedent or published guidance for weaning chronically ventilated children with congenital neuromuscular diseases off mechanical ventilation. When the first ASPIRO participants started showing dramatically improved respiratory function, the investigators initiated efforts to safely wean them off ventilator support, in parallel with primary protocol respiratory outcome measures. A group of experts in respiratory care and physiology and management of children with XLMTM developed an algorithm to safely wean children in the ASPIRO trial off mechanical ventilation as their respiratory muscle strength increased. The algorithm developed for this trial provides recommendations for assessing weaning readiness, a stepwise approach to weaning, and monitoring of children during and after the weaning process.

The major forms of autoimmune myopathies include dermatomyositis (DM), polymyositis (PM), myositis associated with antisynthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). While each of these conditions has unique clinical and histopathological features, they all share an immune-mediated component. These conditions can occur in isolation or can be associated with systemic malignancies or connective tissue disorders (overlap syndromes). As more has been learned about these conditions, it has become clear that traditional classification schemes do not adequately group patients according to shared clinical features and prognosis. Newer classifications are now utilizing myositis-specific autoantibodies which correlate with clinical and histopathological phenotypes and risk of malignancy, and help in offering prognostic information with regard to treatment response. Based on observational data and expert opinion, corticosteroids are considered first-line therapy for DM, PM, ASS, and IMNM, although intravenous immunoglobulin (IVIG) is increasingly being used as initial therapy in IMNM related to statin use. Second-line agents are often required, but further prospective investigation is required regarding the optimal choice and timing of these agents.

Purpose of ReviewSporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset, acquired, muscle disease that can be associated with monoclonal gammopathy or HIV infection. The pathological hallmark of SLONM is the accumulation of nemaline rods in muscle fibers. We review here current knowledge about its presentation, pathophysiology, and management.Recent FindingsSLONM usually manifests with subacutely progressive proximal and axial weakness, but it can also present with chronic progressive weakness mimicking muscular dystrophy. The pathophysiology of the disease remains poorly understood, with evidence pointing to both autoimmune mechanisms and hematological neoplasia. Recent studies have identified histological, proteomic, and transcriptomic alterations that shed light on disease mechanisms and distinguish SLONM from inherited nemaline myopathies. A majority of SLONM patients respond to intravenous immunoglobulins, chemotherapy, or hematopoietic stem cell transplant.SummarySLONM is a treatable myopathy, although its underlying etiology and pathomechanisms remain unclear. A high degree of suspicion should be maintained for this disease to reduce diagnostic delay and treatment in SLONM and facilitate its distinction from inherited nemaline myopathies.

Background A rare muscle disease, GNE myopathy is caused by mutations in the GNE gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression. Methods We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored. Results A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed. Conclusions The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy. Trial registration number : ClinicalTrials.gov (NCT04671472).

Background Monoclonal gammopathy‐associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late‐onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features. Methods Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG‐kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers. Results A 69‐year‐old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG‐kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non‐rimmed vacuoles (0.3% of fibers) containing PAS‐positive, diastase‐labile material consistent with concurrent SLONM and glycogen storage myopathy‐like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma‐cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M‐protein reduction. Further gains followed autologous stem cell transplantation. Conclusion This case expands the MGAM spectrum, highlighting co‐occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.

Background Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking. Methods We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966–2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases. In 6 SLONM patients, we performed a targeted next-generation sequencing (NGS) panel comprising 283 myopathy genes. Results SLONM patients had a mean age at onset of 52 years. The predominant phenotype consisted of weakness and atrophy of proximal upper limbs in 84%, of proximal lower limbs in 80% and both in 67%. Other common symptoms included axial weakness in 68%, as well as dyspnea in 55% and dysphagia in 47% of the patients. In 53% a monoclonal gammopathy of unknown significance (MGUS) was detected in serum. The mean percentage of muscle fibers containing rods was 28% (range 1–63%). In 2 cases ultrastructural analysis was necessary to detect the rods. The most successful treatment in SLONM patients (all with MGUS) was autologous peripheral blood stem cell therapy. A targeted NGS gene panel in 6 SLONM patients (without MGUS) did not reveal causative pathogenic variants. In a comparison of SLONM patients with and without MGUS, the former comprised significantly more males, had more rapid disease progression, and more vacuolar changes in muscle fibers. Interestingly, the muscle biopsy of 2 SLONM patients with MGUS revealed intranuclear rods, whereas this feature was not seen in any of the biopsies from patients without paraproteinemia. Compared to the overall SLONM cohort, significantly more HIV-NM patients were male, with a lower age at onset (mean 34 years). In addition, immunosuppression was more frequently applied with more favorable outcome, and muscle biopsies revealed a significantly higher degree of inflammation and necrosis in this cohort. Similar to SLONM, MGUS was present in half of the HIV-NM patients. Conclusions SLONM presents a challenging, but important differential diagnosis to other neuromuscular diseases of adult onset. Investigations for MGUS and HIV should be performed, as they require distinct but often effective therapeutic approaches. Even though SLONM and HIV-NM show some differences, there exists a large clinico-pathological overlap between the 2 entities.