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.
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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.
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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.
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