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:
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).
2026-07-29 | 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.
2026-07-28 | 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)
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.
2026-05-08 | 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.
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).
2026-07-29 | 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.
2026-07-28 | 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)
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.
2026-05-08 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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