RARE DISEASE
Centronuclear myopathy
Centronuclear myopathy
Centronuclear myopathy
Synonyms: CNM
Synonyms: CNM
Synonyms: CNM
Drug discovery
2
drugs
With orphan designations
Overview
Centronuclear Myopathy (CNM) is a rare genetic neuromuscular disorder characterized by skeletal muscle weakness, atrophy, and displaced nuclei in muscle fibers. Symptoms range from mild hypotonia to severe respiratory and motor impairment, with variable onset (birth to adulthood). Associated features include ptosis, scoliosis, cardiomyopathy, and neuropathy. Caused by mutations in DNM2, BIN1, TTN, or MTM1 genes, inheritance patterns include autosomal dominant, recessive, or X-linked forms [2][4].
Burden
High mortality in severe X-linked forms (30% survival in infancy) [12][20]; chronic disability in milder forms.
Respiratory failure, prolonged ventilator dependence, and recurrent infections drive healthcare costs [4][12].
Limited epidemiological data and heterogeneity hinder targeted interventions [2][4].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
161 drug discovery papers about Centronuclear myopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
161 drug discovery papers about Centronuclear myopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2025-12-29 | Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.
Centronuclear myopathies (CNMs) are rare congenital muscle disorders with no effective treatment. Previous studies showed that tamoxifen improved muscle function in mice modeling CNMs caused by variants in MTM1, BIN1 and DNM2. Here, we investigated whether tamoxifen administration improves muscle function and pathology in the severe recessive Ryr1TM/indel mouse model of RYR1-related CNM. Contractile performance, histological analyses and protein levels were assessed in Ryr1TM/indel mice and control littermates (wild type) treated with either a tamoxifen-enriched diet (65 mg/kg of food) or a control diet for 5 weeks, beginning at 3 weeks of age. Ryr1TM/indel mice displayed muscle weakness, reduced myofiber size and a high number of fibers with nuclei in abnormal position, regardless of the treatment. Force production during repeated contractions was reduced in tamoxifen-treated Ryr1TM/indel mice compared to that in untreated Ryr1TM/indel mice. The levels of CNM proteins (DNM2 and BIN1) were unchanged following the treatment. Tamoxifen did not improve muscle dysfunction, atrophy or histological hallmarks in Ryr1TM/indel mice. Our data indicate that tamoxifen supplementation is not beneficial and may negatively impact muscle function in this model of CNM, suggesting limited therapeutic value for patients with RYR1 mutations.
2025-12-16 | Comparative analysis of viral and development of non-viral muscle-targeted gene delivery systems with application to BIN1-related Centronuclear Myopathy
Analyse comparative des approches virales et développement de systèmes de délivrance génique non viraux ciblant le muscle, avec application à la myopathie centronucléaire liée à BIN1 Les myopathies centronucléaires (CNM) sont des maladies musculaires génétiques rares affectant la structure et la fonction du muscle squelettique. Cette thèse visait à développer des systèmes de délivrance génique spécifiquement ciblés vers le muscle squelettique par des approches virales ou non virales, avec un focus particulier sur la CNM liée à BIN1 (CNM-BIN1). L’analyse comparative d’AAV myotropiques dérivées de l’AAV9 a identifié MyoAAV4A comme le vecteur le plus performant pour la transduction du muscle et du coeur, tout en dé-ciblant le foie. En parallèle, des nanoparticules lipidiques fonctionnalisées avec le peptide MyomP1 (MyomP1-LNPs) ont été développées afin d’obtenir un ciblage musculaire actif et une réduction de la captation hépatique, offrant ainsi une alternative non virale prometteuse. L’utilisation du vecteur optimisé MyoAAV4A pour la thérapie de remplacement du gène BIN1 a permis de restaurer la structure et la fonction musculaires chez des souris CNM-BIN1, même après l’apparition de la maladie, en corrigeant les caractéristiques clés de la CNM telles que la faiblesse et l’atrophie musculaires, grâce à la restauration du réseau des tubules T et des protéines impliquées dans le couplage excitation-contraction. Dans l’ensemble, ce travail propose des plateformes virales et non virales efficaces pour la thérapie génique ciblée du muscle et ouvre de nouvelles perspectives thérapeutiques pour les CNM liées à BIN1 et, plus largement, pour d’autres maladies musculaires génétiques.
2025-11-28 | 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.
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.
2025-12-29 | Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.
Centronuclear myopathies (CNMs) are rare congenital muscle disorders with no effective treatment. Previous studies showed that tamoxifen improved muscle function in mice modeling CNMs caused by variants in MTM1, BIN1 and DNM2. Here, we investigated whether tamoxifen administration improves muscle function and pathology in the severe recessive Ryr1TM/indel mouse model of RYR1-related CNM. Contractile performance, histological analyses and protein levels were assessed in Ryr1TM/indel mice and control littermates (wild type) treated with either a tamoxifen-enriched diet (65 mg/kg of food) or a control diet for 5 weeks, beginning at 3 weeks of age. Ryr1TM/indel mice displayed muscle weakness, reduced myofiber size and a high number of fibers with nuclei in abnormal position, regardless of the treatment. Force production during repeated contractions was reduced in tamoxifen-treated Ryr1TM/indel mice compared to that in untreated Ryr1TM/indel mice. The levels of CNM proteins (DNM2 and BIN1) were unchanged following the treatment. Tamoxifen did not improve muscle dysfunction, atrophy or histological hallmarks in Ryr1TM/indel mice. Our data indicate that tamoxifen supplementation is not beneficial and may negatively impact muscle function in this model of CNM, suggesting limited therapeutic value for patients with RYR1 mutations.
2025-12-16 | Comparative analysis of viral and development of non-viral muscle-targeted gene delivery systems with application to BIN1-related Centronuclear Myopathy
Analyse comparative des approches virales et développement de systèmes de délivrance génique non viraux ciblant le muscle, avec application à la myopathie centronucléaire liée à BIN1 Les myopathies centronucléaires (CNM) sont des maladies musculaires génétiques rares affectant la structure et la fonction du muscle squelettique. Cette thèse visait à développer des systèmes de délivrance génique spécifiquement ciblés vers le muscle squelettique par des approches virales ou non virales, avec un focus particulier sur la CNM liée à BIN1 (CNM-BIN1). L’analyse comparative d’AAV myotropiques dérivées de l’AAV9 a identifié MyoAAV4A comme le vecteur le plus performant pour la transduction du muscle et du coeur, tout en dé-ciblant le foie. En parallèle, des nanoparticules lipidiques fonctionnalisées avec le peptide MyomP1 (MyomP1-LNPs) ont été développées afin d’obtenir un ciblage musculaire actif et une réduction de la captation hépatique, offrant ainsi une alternative non virale prometteuse. L’utilisation du vecteur optimisé MyoAAV4A pour la thérapie de remplacement du gène BIN1 a permis de restaurer la structure et la fonction musculaires chez des souris CNM-BIN1, même après l’apparition de la maladie, en corrigeant les caractéristiques clés de la CNM telles que la faiblesse et l’atrophie musculaires, grâce à la restauration du réseau des tubules T et des protéines impliquées dans le couplage excitation-contraction. Dans l’ensemble, ce travail propose des plateformes virales et non virales efficaces pour la thérapie génique ciblée du muscle et ouvre de nouvelles perspectives thérapeutiques pour les CNM liées à BIN1 et, plus largement, pour d’autres maladies musculaires génétiques.
2025-11-28 | 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.
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Drug Discovery Landscape
2 orphan drug designations for Centronuclear myopathy.
2 orphan drug designations for Centronuclear myopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
5¿-cEtG-sp-cEt5MeU-sp-cEt5MeU-sp-dT-sp-dA-sp-dT-sp-dT-sp-dA-sp-dT-sp-dA-sp-dG-sp-dG-sp-dG-sp-cEt5MeC-sp-cEt5MeU-sp-cEt5MeU-3¿ | oligonucleotides | FDA | 2019-08-05 | — | Dynacure SAS |
5'-cEtG-sp-cEt5MeU-sp-cEt5MeU-sp-dT-sp-dA-sp-dT-sp-dT-sp-dA-sp-dT-sp-dA-sp-dG-sp-dG-sp-dG-sp-cEt5MeC-sp-cEt5MeU-sp-cEt5MeU-3' | oligonucleotides | EMA | 2019-06-28 | — | Dynacure S.A.S. |
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