RARE DISEASE
X-linked centronuclear myopathy
X-linked centronuclear myopathy
X-linked centronuclear myopathy
Synonyms: X-linked myotubular myopathy, XLCNM, XLMTM
Synonyms: X-linked myotubular myopathy, XLCNM, XLMTM
Synonyms: X-linked myotubular myopathy, XLCNM, XLMTM
Drug discovery
3
drugs
With orphan designations
Overview
X-linked centronuclear myopathy (XLMTM) is a severe congenital neuromuscular disorder caused by mutations in the MTM1 gene, leading to skeletal muscle weakness, hypotonia, and respiratory insufficiency. It primarily affects males (1:50,000 births), with prenatal features like polyhydramnios and postnatal ventilator dependence. Diagnosis combines muscle biopsy findings (central nuclei, fiber atrophy) and genetic confirmation. Mortality is high in infancy, though advances in supportive care (mechanical ventilation, gastrostomy) have improved survival. Emerging therapies targeting MTM1 restoration or downstream pathways show preclinical promise [1][5][6][13].
Burden
Mortality: ~44% in first 18 months; survivors face lifelong ventilator dependence (75%) and frequent hospitalizations (35% annual inpatient days) [4][14][18].
Complications: Recurrent infections, liver peliosis, scoliosis, and neurodevelopmental delays (43% with learning disabilities) [9][14][18].
Healthcare utilization: Average 3.7 surgeries in the first year and high caregiver burden [4][9].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
176 drug discovery papers about X-linked centronuclear myopathy, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
176 drug discovery papers about X-linked centronuclear myopathy, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-27 | Beyond Membrane Remodeling: Organelle Crosstalk and Convergent Pathology in Centronuclear Myopathy.
Centronuclear myopathy (CNM) is a genetically heterogenous congenital myopathy traditionally classified as a membrane remodeling disorder. Emerging evidence reveals that centronuclear myopathy mutations converge upon common cellular dysfunction extending beyond membrane trafficking. This review proposes a unified model positioning CNM as a disorder of impaired organelle communication and structural crosstalk. We focus on how mutations in Myotubularin1 (MTM1) and gain-of-function mutations in Dynamin 2 (DNM2) disrupt the triad architecture, leading to aberrant calcium handling, mitochondrial dysfunction, imbalanced reactive oxygen species (ROS) production, and defective autophagy. These dysfunctions are not isolated but form a pathological feedback loop that compromises muscle integrity and regeneration. By identifying shared mechanisms across CNM types, this review positions the disorder as the convergence of organelle stress and cytoskeletal network failure. This perspective reveals novel therapeutic strategies based on the principle that targeting a central pathological node may alleviate systemic dysfunction. However, given the complexity of the organelle feedback loop, a comprehensive, multi-target approach may ultimately be required to achieve full phenotypic rescue across all affected tissues.
2026-04-09 | Pharmacological PIK3C2B inhibition rescues XLMTM phenotype in mouse models and identifies molecular markers of disease.
X-linked myotubular myopathy (XLMTM) is a rare genetic disorder that typically presents at birth with progressive muscle weakness and respiratory difficulties and is caused by myotubularin 1 (MTM1) gene mutations. Here, we examine the role of phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2-β (PIK3C2B), a lipid kinase that interacts with MTM1, in XLMTM in various models. We examined the effect of BLU3797, a highly potent, selective, orally bioavailable PIK3C2B inhibitor, on survival, muscle development, myofiber phenotypes, and gene expression in MTM1-/y mice. PIK3C2B-deficient XLMTM animals demonstrated increased survival, restored muscle function, fewer myofibers with centralized nuclei, and normalization of disease-associated molecular markers. BLU3797 alleviated the XLMTM phenotype in a dose-dependent and reversible manner. Loss of functional PIK3C2B in XLMTM mice promoted a more differentiated, adult-like myofiber profile, which was strongly associated with normalization of disease surrogates and a reduction in markers of early muscle development and regeneration. BLU3797 treatment appears to modulate the expression of miRNAs associated with satellite cell activation and myofiber fusion. These findings indicate that PIK3C2B inhibition with BLU3797 effectively reverses the XLMTM disease phenotype by enhancing muscle function and promoting development toward a more mature state.
2025-12-11 | Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies.
Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in MTM1, DNM2, or BIN1. The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the Mtm1-/y mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities.
2025-11-06 | Myosin inhibition partially rescues the myofibre proteome in X-linked myotubular myopathy.
X-linked myotubular myopathy (XLMTM) due to MTM1 mutations is a rare and often lethal congenital myopathy. Its downstream molecular and cellular mechanisms are currently incompletely understood. The most abundant protein in muscle, myosin, has been implicated in the pathophysiology of other congenital myopathies. Hence, in the present study, we aimed to define whether myosin is also dysfunctional in XLMTM and whether it thus may constitute a potential drug target. To this end, we used skeletal muscle tissue from human patients and canine/mouse models; we performed Mant-ATP chase experiments coupled with X-ray diffraction analyses and LC/MS-based proteomics studies. In XLMTM humans, we found that myosin molecules are structurally disordered and preferably adopt their ATP-consuming biochemical state. This phosphorylation-related (mal)adaptation was mirrored by a striking remodelling of the myofibre energetic proteome in XLMTM dogs. In line with these, we confirmed an accrued myosin ATP consumption in mice lacking MTM1. Hence, we treated these, with a myosin ATPase inhibitor, mavacamten. After a four-week treatment period, we observed a partial restoration of the myofibre proteome, especially proteins involved in cytoskeletal, sarcomeric and energetic pathways. Altogether, our study highlights myosin inhibition as a new potential drug mechanism for the complex XLMTM muscle phenotype.
2025-07-29 | Aberrant lysosomal dynamics disrupt myogenesis via mTORC1 signalling in X-linked myotubular myopathy.
X-linked myotubular myopathy is a severe congenital muscle disorder caused by pathogenic variants in the MTM1 gene, which encodes the phosphoinositide phosphatase myotubularin. Muscle biopsies from patients with X-linked myotubular myopathy exhibit distinctive histopathological features, including small, rounded myofibres with centrally located nuclei, indicating a developmental defect in muscle maturation. While earlier studies have indicated that myotubularin dysfunction causes dysregulation of mechanistic target of rapamycin complex 1 (mTORC1) signalling, the underlying mechanisms and phenotypic impact on human muscle cells remain poorly understood. Currently, there are no approved therapies available for the treatment of this disorder. In this study, we established an induced pluripotent stem cell-based model of X-linked myotubular myopathy using two pairs of isogenic-induced pluripotent stem cells: healthy control versus MTM1-knockout and patient-derived versus gene-corrected induced pluripotent stem cells. Through myogenic differentiation 1-inducible myogenic differentiation, this model successfully recapitulates the key pathological features of X-linked myotubular myopathy, including elevated phosphatidylinositol-3-phosphate levels, hyperactivation of mTORC1 signalling, and increased expression of integrin-β1 and dynamin 2. We identified impaired lysosomal dynamics as a novel pathogenic mechanism in X-linked myotubular myopathy. Our induced pluripotent stem cell-derived X-linked myotubular myopathy myotubes exhibited an abnormal redistribution of lysosomes, with peripheral accumulation, leading to abnormally activated mTORC1 signalling. FYCO1 knockdown, a key regulator of lysosomal trafficking, ameliorated this hyperactivation of mTORC1 signalling. Comprehensive transcriptome analysis revealed distinct gene expression patterns associated with altered mTORC1 signalling and lysosomal localization in X-linked myotubular myopathy myotubes. Network analysis suggested the central role of the mTORC1 signalling pathway and its connections to disrupted muscle development and differentiation. To investigate the influence of mTORC1 signalling and myotubularin deficiency on myogenic differentiation, we established two mouse myoblast models: one with constitutively activated mTORC1 signalling and another with Mtm1 knockout. Increased mTORC1 signalling in mouse myoblasts impaired myogenic differentiation, and this impairment was reversed by the mTORC1 inhibitor rapamycin. Notably, rapamycin treatment also ameliorated the impaired myogenic differentiation observed in Mtm1-knockout mouse myoblasts, supporting the causative role of mTORC1 hyperactivation in X-linked myotubular myopathy pathogenesis. In conclusion, our findings establish the first human cell model of X-linked myotubular myopathy, revealing that myotubularin deficiency leads to impaired lysosomal dynamics, which in turn causes mTORC1 dysregulation, a critical factor in the early stage of myogenic differentiation in X-linked myotubular myopathy. These findings provide new insights into the pathogenesis of X-linked myotubular myopathy and suggest that targeting mTORC1 signalling may be a promising therapeutic strategy for this debilitating disorder.
proteins
2026-05-08 | DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic target.
Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in MTM1 or DNM2, encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in MTM1-CNM patients and Mtm1-/y mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and Mtm1-/y mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In Mtm1-/y mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated Mtm1-/y Dnm2K562E/+ mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in MTM1-CNM.
2015-10-01 | Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton
Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies.
2013-01-09 | Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy
No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1δ4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM.
2006-12-21 | A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy.
In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.
gene therapies
2026-07-29 | A case report of X-linked centronuclear myopathy in a neonate: clinical presentation, therapeutic process, and genetic insights.
X-linked centronuclear myopathy (XLCNM) is a rare neuromuscular disorder that poses significant diagnostic and treatment challenges, particularly in neonates. We present a case of a male infant born at 36 weeks of gestation, weighing 2.1 kg, who was admitted 51 min after birth due to severe asphyxia and low birth weight. Following an emergency cesarean section, the infant required resuscitation, including tracheal intubation and medication administration. Initial evaluations indicated severe respiratory distress and low muscle tone, along with various clinical abnormalities. Laboratory tests suggested potential infection and metabolic distress. Despite comprehensive intensive care, including mechanical ventilation, anti-infection regimens, and nutritional support, the infant continued to experience respiratory difficulties without improvement. Genetic testing via whole exome sequencing identified a rare variant in the MTM1 gene, confirming the diagnosis of XLCNM with an X-linked recessive inheritance pattern. Unfortunately, after extensive treatment and family discussions, the infant's condition failed to stabilize, leading to the difficult decision to withdraw therapy, resulting in the patient's passing. This case underscores the urgent need for early recognition of XLCNM and the critical role of genetic counseling for affected families.
2026-05-01 | Early life nutrition and AAV therapy are determinants of liver disease in X-linked myotubular myopathy
Background: X-linked myotubular myopathy (XLMTM) is a severe neuromuscular disorder caused by pathogenic variants in MTM1 and characterized by profound muscle weakness, technological dependence, and early death. Progressive liver dysfunction is an emerging, potentially fatal consequence of the disease that is not well understood and directly impacts the response to transformative genetic therapies. While preclinical models replicate muscle pathology, they fail to display liver abnormalities. Patients with XLMTM also exhibit several nutrition related complication, including early-onset feeding difficulties requiring enteral nutrition. This study evaluated 1) whether XLMTM mouse models develop liver disease when challenged with patient-relevant dietary exposures, 2) how AAV-based therapies interact with this susceptibility, and 3) novel therapies to treat XLMTM liver disease. Methods: We studied global and hepatocyte-specific Mtm1 Ko mice under standard grain-based chow or purified dietary conditions starting at weaning with or without muscle-directed AAV-based gene replacement therapy. Clinical chemistry, liver histopathology, microbiome analyses and plasma metabolomic and liver transcriptomic analyses were performed. Non-viral lipid nanoparticle (LNP) delivery of MTM1 was evaluated as a rescue strategy. Results: Modified dietary exposure compared to chow revealed liver pathology in XLMTM mice consistent with those thus far reported in patients with XLMTM. Hepatocyte-specific Mtm1 deletion recapitulated key liver abnormalities, supporting a liver autonomous role of Mtm1. AAV therapy increased susceptibility to liver injury in XLMTM mice and induced hepatobiliary changes in wild-type mice. These changes were further associated with unique metabolomic and transcriptomic signatures, and shifts in fecal microbiota due to dietary exposures. Lastly, rescue of the XLMTM liver phenotype with LNP mRNA delivery was achieved in diet-sensitized mice, supporting a targeted strategy to treat XLMTM-associated liver injury. Conclusion: Our findings support a multi-hit model of XLMTM liver disease, reveal a previously underappreciated role of diet in modulating adverse effects of gene therapy, and identify a potential strategy to protect against severe liver injury in patients with XLMTM. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-04-15 | X-linked myotubular myopathy in a neonate: a case report and literature review.
X-linked centronuclear myopathy (XLCNM) is a rare congenital neuromuscular disorder caused by pathogenic variants in MTM1, typically presenting with severe neonatal hypotonia, respiratory failure, and poor survival. Early diagnosis is essential for prognosis and genetic counseling, though clinical recognition is often challenging. We report a male infant, born at 38 + 1 weeks via cesarean section, who presented immediately after birth with apnea, cyanosis, hypotonia, and poor responsiveness. Despite resuscitation and intensive care for neonatal asphyxia and sepsis, he remained ventilator-dependent with persistent hypotonia and feeding difficulties. Laboratory evaluation showed anemia of chronic disease, hypoproteinemia, vitamin D insufficiency, and mild hepatic dysfunction. Imaging revealed laryngomalacia and a patent foramen ovale. Given the family history of neonatal death in a male sibling, whole-exome sequencing (WES) was performed and identified a hemizygous nonsense mutation in MTM1 (NM_000252.2): c.373C > T (p.Gln125Ter), confirming XLCNM. Maternal heterozygosity was verified by Sanger sequencing, consistent with X-linked recessive inheritance. In view of the severe clinical course and poor prognosis, the family declined further treatment. The patient was discharged for palliative care and died shortly after from respiratory failure. This case reveals the importance of early recognition and genetic diagnosis of XLCNM, particularly in neonates with unexplained hypotonia and a suggestive family history. Through our literature review, we emphasize the need for heightened clinical awareness, summarize current therapeutic and research advances, and discusses supportive strategies that may optimize survival and quality of life in affected infants.
2026-02-18 | AAV8 gene therapy and dietary insults together precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy.
Adeno-associated virus (AAV)-mediated liver injury is the primary off-target toxicity observed with viral gene therapy. Understanding of the underlying mechanisms has been hindered by the fact that murine studies poorly model AAV toxicity. The X-linked myotubular myopathy (XLMTM) gene therapy program epitomizes this therapeutic discordance, because a subset of participants treated with AAV8-driven myotubularin (MTM1) gene replacement developed fatal liver injury that was not predicted by preclinical models. Here, we investigated a multihit hypothesis whereby loss of Mtm1 interacts with the postweaning environment to precipitate liver injury in XLMTM mouse models. Mtm1 knockout (KO) mice fed purified ingredient diets manifested liver dysfunction that mirrored patient clinical presentations, including elevated plasma transaminases, altered bile acid composition, and histological features of cholestasis. We further demonstrated a role for MTM1 in maintaining hepatocyte structure and localization of the bile salt export pump. Liver-specific deletion of Mtm1 recapitulated many of these features, supporting a liver-autonomous role for Mtm1. Treatment of diet-sensitized mice with AAV8-driven gene therapy increased the susceptibility of cholestasis in global KO mice and induced liver injury in wild-type mice. Last, as a proof of concept, we treated global KO mice with lipid nanoparticle MTM1 gene replacement, which prevented development of key histopathological liver abnormalities. These findings provide critical insights into the environmental precipitants and molecular mechanisms of liver dysfunction in XLMTM and the adverse events seen in viral gene therapy studies and more broadly offer a framework to model AAV-associated toxicity and identify potential therapeutic interventions.
2025-05-01 | BIN1 gene replacement reverses BIN1-related centronuclear myopathy.
Centronuclear myopathies (CNMs) are severe genetic disorders characterized by generalized muscle weakness associated with organelle mispositioning in myofibers. Most CNM cases are caused by mutations in proteins involved in membrane remodeling, including amphiphysin 2 (BIN1). There is no treatment, and the pathological mechanisms are not understood. Here, we aimed to cure the Bin1-CNM mouse model (Bin1mck-/-) via an adeno-associated virus (AAV)-based gene replacement strategy. Early systemic exogenous BIN1 expression efficiently prevented disease progression. Moreover, BIN1 expression after disease onset reversed all disease signs 4 weeks after treatment, including motor defects, muscle weakness, muscle and myofiber hypotrophy, kyphosis, nuclei and mitochondria misposition, and altered T-tubules network. We then validated the most efficient construct combining a myotropic AAV serotype with the muscle BIN1 isoform. The rescue correlated with the normalization of autophagy and excitation-contraction coupling markers. Cellular and in vivo investigations revealed that different BIN1 natural isoforms shared similar beneficial effects. Artificial constructs coding for separated protein domains rescued different CNM hallmarks. Only the muscle-specific BIN1 isoform combined the different cellular functions of BIN1 on membrane tubulation and dynamin (DNM2) regulation necessary for a full rescue. Overall, this study validates BIN1 gene replacement as a promising strategy to cure BIN1-related CNM.
oligonucleotides
2026-08-14 | Clinical, histopathological, and biomarker characterization of XLMTM and ADCNM: Operational lessons, screening and baseline data of the Unite-CNM study.
BackgroundX-linked myotubular myopathy (XLMTM) and autosomal dominant centronuclear myopathy (ADCNM) are rare neuromuscular disorders characterized by severe weakness and respiratory impairment and have recently been the focus of therapeutic development. Robust baseline data are essential to understand disease trajectories and enable trial readiness. We present baseline clinical, functional, and biomarker findings from the terminated Unite-CNM trial (NCT04033159), a basket study of the antisense oligonucleotide DYN101, designed to modulate DNM2 expression in adolescents and adults with XLMTM or ADCNM.MethodsScreening and baseline evaluations included medical history, patient-reported outcomes, quantitative muscle strength and motor function, respiratory testing, muscle ultrasound and histology, and biomarker analyses (DNM2 protein, creatinine, creatine kinase, cystatin C, myostatin, and microRNAs) in plasma and muscle.ResultsTwenty-six patients were screened (15 DNM2, 11 MTM1); 14 entered the study. Patient-reported measures highlighted swallowing challenges and variable personal goals. Baseline respiratory impairment was variable in DNM2 and female MTM1 patients but consistently reduced in males with MTM1 (FVC% and FEV1% stable over follow-up to 78 weeks). MFM32 scores were similar across genotypes and sexes, while Myogrip strength was reduced versus age norms yet stable longitudinally. Muscle pathology was comparable across groups. Biomarker analyses showed altered DNM2 protein, reduced myostatin, and specific abnormalities in creatinine, creatine kinase, cystatin C, and microRNAs.ConclusionThis dataset provides valuable phenotypic, functional, and biomarker characterization of adult XLMTM and ADCNM, emphasizes the importance of baseline data for ultrarare disease trials, and highlights the need for protocol flexibility in response to safety signals and disruptions (e.g. COVID-19).
2026-01-28 | P18 N-of-1 ASO therapeutic development for ultra-rare deep intronic mutations in X-linked myotubular myopathy
X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital neuromuscular disorder caused by mutations in the MTM1 gene. Affected infants typically present with severe hypotonia and respiratory failure, with up to 50% mortality in the first year of life. No approved disease-modifying therapies are currently available. At Great Ormond Street Hospital, through the Highly Specialised Congenital Myopathy Service, we have identified two ultra-rare deep intronic MTM1 mutations: one previously reported (c.1468-577A>G) and one novel (c.342+575C>G). Both mutations cause pseudo-exon inclusion and introduce premature stop codons, resulting in loss of MTM1 protein. We propose to develop two N-of-1 exon-skipping antisense oligonucleotide (ASO) therapies tailored to these mutations. By inducing skipping of the pseudo-exons, the ASOs aim to restore normal splicing and functional MTM1 protein expression. ASOs targeting both variants have already demonstrated effective pseudo-exon skipping and restoration of MTM1 protein in patient-derived fibroblasts. Building on these results, we will further optimise the ASO sequences and assess their efficacy and safety in MyoD-reprogrammed muscle cells and hepatocytes differentiated from patient-specific iPSCs, with the goal of demonstrating therapeutic benefit in both muscle and liver tissues.
2025-07-03 | Exon skipping peptide-conjugated morpholinos downregulate dynamin 2 to rescue centronuclear myopathy.
Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and disorganization of myofibres. These conditions can result from dominant mutations in the DNM2 gene encoding the GTPase dynamin, making them potential targets for antisense therapy. Preclinical studies suggested decreasing DNM2 as a therapy but a recent clinical trial with antisense oligonucleotides did not effectively address the disease and showed some non-muscle toxicity. Here, to promote DNM2 downregulation in muscle versus other tissues, we used an exon skipping peptide-conjugated phosphorodiamidate morpholino (PPMO) targeting Dnm2 exon 6 splicing in the Dnm2R369W/+ mouse model for the moderate CNM form. Intravenous administration of PPMOs at an early age (4 weeks) significantly downregulated intact (i.e. normally spliced) Dnm2 mRNA (∼50%) and DNM2 protein levels in muscle. This intervention led to a rescue of muscle force, thereby preventing disease progression. PPMO administration at a later age (8 weeks), when mice demonstrated established phenotypes, efficiently decreased intact Dnm2 mRNA and protein levels in muscle, resulting in reversal of the disease phenotype and significant improvement in muscle force (from 11 mN/mg to nearly 16 mN/mg). Overall, our results indicate that PPMOs targeting Dnm2 splicing effectively decrease intact Dnm2 mRNA and protein levels in muscle and rescue muscle force in Dnm2R369W/+ mice, suggesting a promising translational approach for patients with DNM2 mutations and potentially other forms of CNM. More generally, it provides the concept of using the exon skipping strategy to decrease the protein expression of a target gene, rather than producing a shorter functional protein as is generally done.
2024-06-13 | Amphiphysin-2 (BIN1) functions and defects in cardiac and skeletal muscle.
Amphiphysin-2 is a ubiquitously expressed protein also known as bridging integrator 1 (BIN1), playing a critical role in membrane remodeling, trafficking, and cytoskeleton dynamics in a wide range of tissues. Mutations in the gene encoding BIN1 cause centronuclear myopathies (CNM), and recent evidence has implicated BIN1 in heart failure, underlining its crucial role in both skeletal and cardiac muscle. Furthermore, altered expression of BIN1 is linked to an increased risk of late-onset Alzheimer's disease and several types of cancer, including breast, colon, prostate, and lung cancers. Recently, the first proof-of-concept for potential therapeutic strategies modulating BIN1 were obtained for muscle diseases. In this review article, we discuss the similarities and differences in BIN1's functions in cardiac and skeletal muscle, along with its associated diseases and potential therapies.
2022-11-17 | Differential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy.
Dynamin 2 mechanoenzyme is a key regulator of membrane remodeling and gain-of-function mutations in its gene cause centronuclear myopathies. Here, we investigate the functions of dynamin 2 isoforms and their associated phenotypes and, specifically, the ubiquitous and muscle-specific dynamin 2 isoforms expressed in skeletal muscle. In cell-based assays, we show that a centronuclear myopathy-related mutation in the ubiquitous but not the muscle-specific dynamin 2 isoform causes increased membrane fission. In vivo, overexpressing the ubiquitous dynamin 2 isoform correlates with severe forms of centronuclear myopathy, while overexpressing the muscle-specific isoform leads to hallmarks seen in milder cases of the disease. Previous mouse studies suggested that reduction of the total dynamin 2 pool could be therapeutic for centronuclear myopathies. Here, dynamin 2 splice switching from muscle-specific to ubiquitous dynamin 2 aggravated the phenotype of a severe X-linked form of centronuclear myopathy caused by loss-of-function of the MTM1 phosphatase, supporting the importance of targeting the ubiquitous isoform for efficient therapy in muscle. Our results highlight that the ubiquitous and not the muscle-specific dynamin 2 isoform is the main modifier contributing to centronuclear myopathy pathology.
other
2026-07-28 | Uncovering the immunological determinants of progressive liver disease in X-linked Myotubular Myopathy 2260077
Abstract Introduction X-linked myotubular myopathy (XLMTM) is a fatal cogenital neuromuscular disease caused by mutations in MTM1. While adeno-associated virus (AAV) gene therapy has shown promising outcomes in the first clinical trial for XLMTM, its progress has been halted by unexplained and often lethal hepatotoxicity. XLMTM is hallmarked by an accumulation of phosphatidylinositol 3-phosphate, which is a known regulator of macrophage phagocytic activities. Given that Mtm1 is also highly expressed in resident liver myeloid cells, we hypothesized that MTM1 deficiency disrupts intrinsic myeloid regulatory processes, creating a hyperinflammatory microenvironment that sensitizes the liver to gene therapy-associated injury. Methods We compared wild-type (WT) and Mtm1 knock-out (KO) mice challenged with H1N1 infection or bacterial endotoxemia (LPS) starting at postnatal day 21 to unmask latent immunopathology. Plasma cytokines analysis, liver histopathology and immunophenotyping were performed at the clinical endpoint. Results Following H1N1 infection, KO mice exhibited reduced survival (within a week post infection) and heightened liver inflammation characterized by F4/80+ myeloid cell infiltration alongside a systemic cytokine storm. This hyper-inflammatory state was starkly highlighted during endotoxemia, where a sublethal dose of LPS for WT mice was fatal to all KO mice within four hours and associated with a 2-fold increase in plasma IL-6 concentrations. This extreme sensitivity to immune stimuli is consistent with the predicted hyper-inflammatory state of myeloid sentinels due to the lack of MTM1. Conclusion The absence of MTM1 heightens the susceptibility to severe, immune-mediated inflammatory damage during early life, underscoring the urgent need for immunomodulatory co-therapies. Future work using macrophage models will serve as a crucial platform to test targeted immunomodulatory therapies designed to prevent this lethal inflammatory response and improve the safety of AAV gene therapy for XLMTM patients. Funding Source CIHR Topic Categories Immune Mechanisms of Human Disease (HUM)
2011-05-23 | Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice.
X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency.
small molecules
2026-05-27 | Beyond Membrane Remodeling: Organelle Crosstalk and Convergent Pathology in Centronuclear Myopathy.
Centronuclear myopathy (CNM) is a genetically heterogenous congenital myopathy traditionally classified as a membrane remodeling disorder. Emerging evidence reveals that centronuclear myopathy mutations converge upon common cellular dysfunction extending beyond membrane trafficking. This review proposes a unified model positioning CNM as a disorder of impaired organelle communication and structural crosstalk. We focus on how mutations in Myotubularin1 (MTM1) and gain-of-function mutations in Dynamin 2 (DNM2) disrupt the triad architecture, leading to aberrant calcium handling, mitochondrial dysfunction, imbalanced reactive oxygen species (ROS) production, and defective autophagy. These dysfunctions are not isolated but form a pathological feedback loop that compromises muscle integrity and regeneration. By identifying shared mechanisms across CNM types, this review positions the disorder as the convergence of organelle stress and cytoskeletal network failure. This perspective reveals novel therapeutic strategies based on the principle that targeting a central pathological node may alleviate systemic dysfunction. However, given the complexity of the organelle feedback loop, a comprehensive, multi-target approach may ultimately be required to achieve full phenotypic rescue across all affected tissues.
2026-04-09 | Pharmacological PIK3C2B inhibition rescues XLMTM phenotype in mouse models and identifies molecular markers of disease.
X-linked myotubular myopathy (XLMTM) is a rare genetic disorder that typically presents at birth with progressive muscle weakness and respiratory difficulties and is caused by myotubularin 1 (MTM1) gene mutations. Here, we examine the role of phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2-β (PIK3C2B), a lipid kinase that interacts with MTM1, in XLMTM in various models. We examined the effect of BLU3797, a highly potent, selective, orally bioavailable PIK3C2B inhibitor, on survival, muscle development, myofiber phenotypes, and gene expression in MTM1-/y mice. PIK3C2B-deficient XLMTM animals demonstrated increased survival, restored muscle function, fewer myofibers with centralized nuclei, and normalization of disease-associated molecular markers. BLU3797 alleviated the XLMTM phenotype in a dose-dependent and reversible manner. Loss of functional PIK3C2B in XLMTM mice promoted a more differentiated, adult-like myofiber profile, which was strongly associated with normalization of disease surrogates and a reduction in markers of early muscle development and regeneration. BLU3797 treatment appears to modulate the expression of miRNAs associated with satellite cell activation and myofiber fusion. These findings indicate that PIK3C2B inhibition with BLU3797 effectively reverses the XLMTM disease phenotype by enhancing muscle function and promoting development toward a more mature state.
2025-12-11 | Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies.
Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in MTM1, DNM2, or BIN1. The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the Mtm1-/y mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities.
2025-11-06 | Myosin inhibition partially rescues the myofibre proteome in X-linked myotubular myopathy.
X-linked myotubular myopathy (XLMTM) due to MTM1 mutations is a rare and often lethal congenital myopathy. Its downstream molecular and cellular mechanisms are currently incompletely understood. The most abundant protein in muscle, myosin, has been implicated in the pathophysiology of other congenital myopathies. Hence, in the present study, we aimed to define whether myosin is also dysfunctional in XLMTM and whether it thus may constitute a potential drug target. To this end, we used skeletal muscle tissue from human patients and canine/mouse models; we performed Mant-ATP chase experiments coupled with X-ray diffraction analyses and LC/MS-based proteomics studies. In XLMTM humans, we found that myosin molecules are structurally disordered and preferably adopt their ATP-consuming biochemical state. This phosphorylation-related (mal)adaptation was mirrored by a striking remodelling of the myofibre energetic proteome in XLMTM dogs. In line with these, we confirmed an accrued myosin ATP consumption in mice lacking MTM1. Hence, we treated these, with a myosin ATPase inhibitor, mavacamten. After a four-week treatment period, we observed a partial restoration of the myofibre proteome, especially proteins involved in cytoskeletal, sarcomeric and energetic pathways. Altogether, our study highlights myosin inhibition as a new potential drug mechanism for the complex XLMTM muscle phenotype.
2025-07-29 | Aberrant lysosomal dynamics disrupt myogenesis via mTORC1 signalling in X-linked myotubular myopathy.
X-linked myotubular myopathy is a severe congenital muscle disorder caused by pathogenic variants in the MTM1 gene, which encodes the phosphoinositide phosphatase myotubularin. Muscle biopsies from patients with X-linked myotubular myopathy exhibit distinctive histopathological features, including small, rounded myofibres with centrally located nuclei, indicating a developmental defect in muscle maturation. While earlier studies have indicated that myotubularin dysfunction causes dysregulation of mechanistic target of rapamycin complex 1 (mTORC1) signalling, the underlying mechanisms and phenotypic impact on human muscle cells remain poorly understood. Currently, there are no approved therapies available for the treatment of this disorder. In this study, we established an induced pluripotent stem cell-based model of X-linked myotubular myopathy using two pairs of isogenic-induced pluripotent stem cells: healthy control versus MTM1-knockout and patient-derived versus gene-corrected induced pluripotent stem cells. Through myogenic differentiation 1-inducible myogenic differentiation, this model successfully recapitulates the key pathological features of X-linked myotubular myopathy, including elevated phosphatidylinositol-3-phosphate levels, hyperactivation of mTORC1 signalling, and increased expression of integrin-β1 and dynamin 2. We identified impaired lysosomal dynamics as a novel pathogenic mechanism in X-linked myotubular myopathy. Our induced pluripotent stem cell-derived X-linked myotubular myopathy myotubes exhibited an abnormal redistribution of lysosomes, with peripheral accumulation, leading to abnormally activated mTORC1 signalling. FYCO1 knockdown, a key regulator of lysosomal trafficking, ameliorated this hyperactivation of mTORC1 signalling. Comprehensive transcriptome analysis revealed distinct gene expression patterns associated with altered mTORC1 signalling and lysosomal localization in X-linked myotubular myopathy myotubes. Network analysis suggested the central role of the mTORC1 signalling pathway and its connections to disrupted muscle development and differentiation. To investigate the influence of mTORC1 signalling and myotubularin deficiency on myogenic differentiation, we established two mouse myoblast models: one with constitutively activated mTORC1 signalling and another with Mtm1 knockout. Increased mTORC1 signalling in mouse myoblasts impaired myogenic differentiation, and this impairment was reversed by the mTORC1 inhibitor rapamycin. Notably, rapamycin treatment also ameliorated the impaired myogenic differentiation observed in Mtm1-knockout mouse myoblasts, supporting the causative role of mTORC1 hyperactivation in X-linked myotubular myopathy pathogenesis. In conclusion, our findings establish the first human cell model of X-linked myotubular myopathy, revealing that myotubularin deficiency leads to impaired lysosomal dynamics, which in turn causes mTORC1 dysregulation, a critical factor in the early stage of myogenic differentiation in X-linked myotubular myopathy. These findings provide new insights into the pathogenesis of X-linked myotubular myopathy and suggest that targeting mTORC1 signalling may be a promising therapeutic strategy for this debilitating disorder.
proteins
2026-05-08 | DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic target.
Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in MTM1 or DNM2, encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in MTM1-CNM patients and Mtm1-/y mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and Mtm1-/y mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In Mtm1-/y mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated Mtm1-/y Dnm2K562E/+ mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in MTM1-CNM.
2015-10-01 | Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton
Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies.
2013-01-09 | Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy
No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1δ4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM.
2006-12-21 | A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy.
In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.
gene therapies
2026-07-29 | A case report of X-linked centronuclear myopathy in a neonate: clinical presentation, therapeutic process, and genetic insights.
X-linked centronuclear myopathy (XLCNM) is a rare neuromuscular disorder that poses significant diagnostic and treatment challenges, particularly in neonates. We present a case of a male infant born at 36 weeks of gestation, weighing 2.1 kg, who was admitted 51 min after birth due to severe asphyxia and low birth weight. Following an emergency cesarean section, the infant required resuscitation, including tracheal intubation and medication administration. Initial evaluations indicated severe respiratory distress and low muscle tone, along with various clinical abnormalities. Laboratory tests suggested potential infection and metabolic distress. Despite comprehensive intensive care, including mechanical ventilation, anti-infection regimens, and nutritional support, the infant continued to experience respiratory difficulties without improvement. Genetic testing via whole exome sequencing identified a rare variant in the MTM1 gene, confirming the diagnosis of XLCNM with an X-linked recessive inheritance pattern. Unfortunately, after extensive treatment and family discussions, the infant's condition failed to stabilize, leading to the difficult decision to withdraw therapy, resulting in the patient's passing. This case underscores the urgent need for early recognition of XLCNM and the critical role of genetic counseling for affected families.
2026-05-01 | Early life nutrition and AAV therapy are determinants of liver disease in X-linked myotubular myopathy
Background: X-linked myotubular myopathy (XLMTM) is a severe neuromuscular disorder caused by pathogenic variants in MTM1 and characterized by profound muscle weakness, technological dependence, and early death. Progressive liver dysfunction is an emerging, potentially fatal consequence of the disease that is not well understood and directly impacts the response to transformative genetic therapies. While preclinical models replicate muscle pathology, they fail to display liver abnormalities. Patients with XLMTM also exhibit several nutrition related complication, including early-onset feeding difficulties requiring enteral nutrition. This study evaluated 1) whether XLMTM mouse models develop liver disease when challenged with patient-relevant dietary exposures, 2) how AAV-based therapies interact with this susceptibility, and 3) novel therapies to treat XLMTM liver disease. Methods: We studied global and hepatocyte-specific Mtm1 Ko mice under standard grain-based chow or purified dietary conditions starting at weaning with or without muscle-directed AAV-based gene replacement therapy. Clinical chemistry, liver histopathology, microbiome analyses and plasma metabolomic and liver transcriptomic analyses were performed. Non-viral lipid nanoparticle (LNP) delivery of MTM1 was evaluated as a rescue strategy. Results: Modified dietary exposure compared to chow revealed liver pathology in XLMTM mice consistent with those thus far reported in patients with XLMTM. Hepatocyte-specific Mtm1 deletion recapitulated key liver abnormalities, supporting a liver autonomous role of Mtm1. AAV therapy increased susceptibility to liver injury in XLMTM mice and induced hepatobiliary changes in wild-type mice. These changes were further associated with unique metabolomic and transcriptomic signatures, and shifts in fecal microbiota due to dietary exposures. Lastly, rescue of the XLMTM liver phenotype with LNP mRNA delivery was achieved in diet-sensitized mice, supporting a targeted strategy to treat XLMTM-associated liver injury. Conclusion: Our findings support a multi-hit model of XLMTM liver disease, reveal a previously underappreciated role of diet in modulating adverse effects of gene therapy, and identify a potential strategy to protect against severe liver injury in patients with XLMTM. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-04-15 | X-linked myotubular myopathy in a neonate: a case report and literature review.
X-linked centronuclear myopathy (XLCNM) is a rare congenital neuromuscular disorder caused by pathogenic variants in MTM1, typically presenting with severe neonatal hypotonia, respiratory failure, and poor survival. Early diagnosis is essential for prognosis and genetic counseling, though clinical recognition is often challenging. We report a male infant, born at 38 + 1 weeks via cesarean section, who presented immediately after birth with apnea, cyanosis, hypotonia, and poor responsiveness. Despite resuscitation and intensive care for neonatal asphyxia and sepsis, he remained ventilator-dependent with persistent hypotonia and feeding difficulties. Laboratory evaluation showed anemia of chronic disease, hypoproteinemia, vitamin D insufficiency, and mild hepatic dysfunction. Imaging revealed laryngomalacia and a patent foramen ovale. Given the family history of neonatal death in a male sibling, whole-exome sequencing (WES) was performed and identified a hemizygous nonsense mutation in MTM1 (NM_000252.2): c.373C > T (p.Gln125Ter), confirming XLCNM. Maternal heterozygosity was verified by Sanger sequencing, consistent with X-linked recessive inheritance. In view of the severe clinical course and poor prognosis, the family declined further treatment. The patient was discharged for palliative care and died shortly after from respiratory failure. This case reveals the importance of early recognition and genetic diagnosis of XLCNM, particularly in neonates with unexplained hypotonia and a suggestive family history. Through our literature review, we emphasize the need for heightened clinical awareness, summarize current therapeutic and research advances, and discusses supportive strategies that may optimize survival and quality of life in affected infants.
2026-02-18 | AAV8 gene therapy and dietary insults together precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy.
Adeno-associated virus (AAV)-mediated liver injury is the primary off-target toxicity observed with viral gene therapy. Understanding of the underlying mechanisms has been hindered by the fact that murine studies poorly model AAV toxicity. The X-linked myotubular myopathy (XLMTM) gene therapy program epitomizes this therapeutic discordance, because a subset of participants treated with AAV8-driven myotubularin (MTM1) gene replacement developed fatal liver injury that was not predicted by preclinical models. Here, we investigated a multihit hypothesis whereby loss of Mtm1 interacts with the postweaning environment to precipitate liver injury in XLMTM mouse models. Mtm1 knockout (KO) mice fed purified ingredient diets manifested liver dysfunction that mirrored patient clinical presentations, including elevated plasma transaminases, altered bile acid composition, and histological features of cholestasis. We further demonstrated a role for MTM1 in maintaining hepatocyte structure and localization of the bile salt export pump. Liver-specific deletion of Mtm1 recapitulated many of these features, supporting a liver-autonomous role for Mtm1. Treatment of diet-sensitized mice with AAV8-driven gene therapy increased the susceptibility of cholestasis in global KO mice and induced liver injury in wild-type mice. Last, as a proof of concept, we treated global KO mice with lipid nanoparticle MTM1 gene replacement, which prevented development of key histopathological liver abnormalities. These findings provide critical insights into the environmental precipitants and molecular mechanisms of liver dysfunction in XLMTM and the adverse events seen in viral gene therapy studies and more broadly offer a framework to model AAV-associated toxicity and identify potential therapeutic interventions.
2025-05-01 | BIN1 gene replacement reverses BIN1-related centronuclear myopathy.
Centronuclear myopathies (CNMs) are severe genetic disorders characterized by generalized muscle weakness associated with organelle mispositioning in myofibers. Most CNM cases are caused by mutations in proteins involved in membrane remodeling, including amphiphysin 2 (BIN1). There is no treatment, and the pathological mechanisms are not understood. Here, we aimed to cure the Bin1-CNM mouse model (Bin1mck-/-) via an adeno-associated virus (AAV)-based gene replacement strategy. Early systemic exogenous BIN1 expression efficiently prevented disease progression. Moreover, BIN1 expression after disease onset reversed all disease signs 4 weeks after treatment, including motor defects, muscle weakness, muscle and myofiber hypotrophy, kyphosis, nuclei and mitochondria misposition, and altered T-tubules network. We then validated the most efficient construct combining a myotropic AAV serotype with the muscle BIN1 isoform. The rescue correlated with the normalization of autophagy and excitation-contraction coupling markers. Cellular and in vivo investigations revealed that different BIN1 natural isoforms shared similar beneficial effects. Artificial constructs coding for separated protein domains rescued different CNM hallmarks. Only the muscle-specific BIN1 isoform combined the different cellular functions of BIN1 on membrane tubulation and dynamin (DNM2) regulation necessary for a full rescue. Overall, this study validates BIN1 gene replacement as a promising strategy to cure BIN1-related CNM.
oligonucleotides
2026-08-14 | Clinical, histopathological, and biomarker characterization of XLMTM and ADCNM: Operational lessons, screening and baseline data of the Unite-CNM study.
BackgroundX-linked myotubular myopathy (XLMTM) and autosomal dominant centronuclear myopathy (ADCNM) are rare neuromuscular disorders characterized by severe weakness and respiratory impairment and have recently been the focus of therapeutic development. Robust baseline data are essential to understand disease trajectories and enable trial readiness. We present baseline clinical, functional, and biomarker findings from the terminated Unite-CNM trial (NCT04033159), a basket study of the antisense oligonucleotide DYN101, designed to modulate DNM2 expression in adolescents and adults with XLMTM or ADCNM.MethodsScreening and baseline evaluations included medical history, patient-reported outcomes, quantitative muscle strength and motor function, respiratory testing, muscle ultrasound and histology, and biomarker analyses (DNM2 protein, creatinine, creatine kinase, cystatin C, myostatin, and microRNAs) in plasma and muscle.ResultsTwenty-six patients were screened (15 DNM2, 11 MTM1); 14 entered the study. Patient-reported measures highlighted swallowing challenges and variable personal goals. Baseline respiratory impairment was variable in DNM2 and female MTM1 patients but consistently reduced in males with MTM1 (FVC% and FEV1% stable over follow-up to 78 weeks). MFM32 scores were similar across genotypes and sexes, while Myogrip strength was reduced versus age norms yet stable longitudinally. Muscle pathology was comparable across groups. Biomarker analyses showed altered DNM2 protein, reduced myostatin, and specific abnormalities in creatinine, creatine kinase, cystatin C, and microRNAs.ConclusionThis dataset provides valuable phenotypic, functional, and biomarker characterization of adult XLMTM and ADCNM, emphasizes the importance of baseline data for ultrarare disease trials, and highlights the need for protocol flexibility in response to safety signals and disruptions (e.g. COVID-19).
2026-01-28 | P18 N-of-1 ASO therapeutic development for ultra-rare deep intronic mutations in X-linked myotubular myopathy
X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital neuromuscular disorder caused by mutations in the MTM1 gene. Affected infants typically present with severe hypotonia and respiratory failure, with up to 50% mortality in the first year of life. No approved disease-modifying therapies are currently available. At Great Ormond Street Hospital, through the Highly Specialised Congenital Myopathy Service, we have identified two ultra-rare deep intronic MTM1 mutations: one previously reported (c.1468-577A>G) and one novel (c.342+575C>G). Both mutations cause pseudo-exon inclusion and introduce premature stop codons, resulting in loss of MTM1 protein. We propose to develop two N-of-1 exon-skipping antisense oligonucleotide (ASO) therapies tailored to these mutations. By inducing skipping of the pseudo-exons, the ASOs aim to restore normal splicing and functional MTM1 protein expression. ASOs targeting both variants have already demonstrated effective pseudo-exon skipping and restoration of MTM1 protein in patient-derived fibroblasts. Building on these results, we will further optimise the ASO sequences and assess their efficacy and safety in MyoD-reprogrammed muscle cells and hepatocytes differentiated from patient-specific iPSCs, with the goal of demonstrating therapeutic benefit in both muscle and liver tissues.
2025-07-03 | Exon skipping peptide-conjugated morpholinos downregulate dynamin 2 to rescue centronuclear myopathy.
Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and disorganization of myofibres. These conditions can result from dominant mutations in the DNM2 gene encoding the GTPase dynamin, making them potential targets for antisense therapy. Preclinical studies suggested decreasing DNM2 as a therapy but a recent clinical trial with antisense oligonucleotides did not effectively address the disease and showed some non-muscle toxicity. Here, to promote DNM2 downregulation in muscle versus other tissues, we used an exon skipping peptide-conjugated phosphorodiamidate morpholino (PPMO) targeting Dnm2 exon 6 splicing in the Dnm2R369W/+ mouse model for the moderate CNM form. Intravenous administration of PPMOs at an early age (4 weeks) significantly downregulated intact (i.e. normally spliced) Dnm2 mRNA (∼50%) and DNM2 protein levels in muscle. This intervention led to a rescue of muscle force, thereby preventing disease progression. PPMO administration at a later age (8 weeks), when mice demonstrated established phenotypes, efficiently decreased intact Dnm2 mRNA and protein levels in muscle, resulting in reversal of the disease phenotype and significant improvement in muscle force (from 11 mN/mg to nearly 16 mN/mg). Overall, our results indicate that PPMOs targeting Dnm2 splicing effectively decrease intact Dnm2 mRNA and protein levels in muscle and rescue muscle force in Dnm2R369W/+ mice, suggesting a promising translational approach for patients with DNM2 mutations and potentially other forms of CNM. More generally, it provides the concept of using the exon skipping strategy to decrease the protein expression of a target gene, rather than producing a shorter functional protein as is generally done.
2024-06-13 | Amphiphysin-2 (BIN1) functions and defects in cardiac and skeletal muscle.
Amphiphysin-2 is a ubiquitously expressed protein also known as bridging integrator 1 (BIN1), playing a critical role in membrane remodeling, trafficking, and cytoskeleton dynamics in a wide range of tissues. Mutations in the gene encoding BIN1 cause centronuclear myopathies (CNM), and recent evidence has implicated BIN1 in heart failure, underlining its crucial role in both skeletal and cardiac muscle. Furthermore, altered expression of BIN1 is linked to an increased risk of late-onset Alzheimer's disease and several types of cancer, including breast, colon, prostate, and lung cancers. Recently, the first proof-of-concept for potential therapeutic strategies modulating BIN1 were obtained for muscle diseases. In this review article, we discuss the similarities and differences in BIN1's functions in cardiac and skeletal muscle, along with its associated diseases and potential therapies.
2022-11-17 | Differential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy.
Dynamin 2 mechanoenzyme is a key regulator of membrane remodeling and gain-of-function mutations in its gene cause centronuclear myopathies. Here, we investigate the functions of dynamin 2 isoforms and their associated phenotypes and, specifically, the ubiquitous and muscle-specific dynamin 2 isoforms expressed in skeletal muscle. In cell-based assays, we show that a centronuclear myopathy-related mutation in the ubiquitous but not the muscle-specific dynamin 2 isoform causes increased membrane fission. In vivo, overexpressing the ubiquitous dynamin 2 isoform correlates with severe forms of centronuclear myopathy, while overexpressing the muscle-specific isoform leads to hallmarks seen in milder cases of the disease. Previous mouse studies suggested that reduction of the total dynamin 2 pool could be therapeutic for centronuclear myopathies. Here, dynamin 2 splice switching from muscle-specific to ubiquitous dynamin 2 aggravated the phenotype of a severe X-linked form of centronuclear myopathy caused by loss-of-function of the MTM1 phosphatase, supporting the importance of targeting the ubiquitous isoform for efficient therapy in muscle. Our results highlight that the ubiquitous and not the muscle-specific dynamin 2 isoform is the main modifier contributing to centronuclear myopathy pathology.
other
2026-07-28 | Uncovering the immunological determinants of progressive liver disease in X-linked Myotubular Myopathy 2260077
Abstract Introduction X-linked myotubular myopathy (XLMTM) is a fatal cogenital neuromuscular disease caused by mutations in MTM1. While adeno-associated virus (AAV) gene therapy has shown promising outcomes in the first clinical trial for XLMTM, its progress has been halted by unexplained and often lethal hepatotoxicity. XLMTM is hallmarked by an accumulation of phosphatidylinositol 3-phosphate, which is a known regulator of macrophage phagocytic activities. Given that Mtm1 is also highly expressed in resident liver myeloid cells, we hypothesized that MTM1 deficiency disrupts intrinsic myeloid regulatory processes, creating a hyperinflammatory microenvironment that sensitizes the liver to gene therapy-associated injury. Methods We compared wild-type (WT) and Mtm1 knock-out (KO) mice challenged with H1N1 infection or bacterial endotoxemia (LPS) starting at postnatal day 21 to unmask latent immunopathology. Plasma cytokines analysis, liver histopathology and immunophenotyping were performed at the clinical endpoint. Results Following H1N1 infection, KO mice exhibited reduced survival (within a week post infection) and heightened liver inflammation characterized by F4/80+ myeloid cell infiltration alongside a systemic cytokine storm. This hyper-inflammatory state was starkly highlighted during endotoxemia, where a sublethal dose of LPS for WT mice was fatal to all KO mice within four hours and associated with a 2-fold increase in plasma IL-6 concentrations. This extreme sensitivity to immune stimuli is consistent with the predicted hyper-inflammatory state of myeloid sentinels due to the lack of MTM1. Conclusion The absence of MTM1 heightens the susceptibility to severe, immune-mediated inflammatory damage during early life, underscoring the urgent need for immunomodulatory co-therapies. Future work using macrophage models will serve as a crucial platform to test targeted immunomodulatory therapies designed to prevent this lethal inflammatory response and improve the safety of AAV gene therapy for XLMTM patients. Funding Source CIHR Topic Categories Immune Mechanisms of Human Disease (HUM)
2011-05-23 | Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice.
X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency.
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Drug Discovery Landscape
3 orphan drug designations for X-linked centronuclear myopathy.
3 orphan drug designations for X-linked centronuclear myopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a nonreplicating recombinant adeno-associated virus gene therapy vector expressing human MTM1 gene | gene therapies | FDA | 2024-10-22 | — | Astellas Gene Therapies, Inc. |
Adeno-associated viral vector serotype 8 containing the human MTM1 gene | gene therapies | EMA | 2015-08-10 | — | Astellas Pharma Europe B.V. |
non-replicating adeno-associated viral vector, serotype 8, expressing human myotubularin gene | gene therapies | FDA | 2014-12-03 | — | Astellas Gene Therapies, Inc. |
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