Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

Natural history of a mouse model of X-linked myotubular myopathy

X-linked myotubular myopathy is a severe monogenetic disorder of the skeletal muscle caused by loss of expression/function mutations in the MTM1 (myotubularin) gene. There is a growing understanding of the pathologic and molecular abnormalities associated with loss of MTM1, and emerging therapeutic strategies that are in the process of translation to patients. Much of these data have been uncovered through experimentation in pre-clinical animal models of the disease. The most widely used model is an Mtm1 gene knockout mouse line; this line faithfully recapitulates the salient genetic and pathologic features of the disease. Despite the advances in aspects of XLMTM, there remain many unknowns related to disease pathomechanisms and to understanding of MTM1’s function in normal muscle development, and a continued need for therapy identification and development. To address these barriers, and to lay the groundwork for future study, we performed a natural history study of the Mtm1 knockout mouse model of XLMTM. We show that certain molecular and pathologic changes precede overt phenotypic changes, while others, including abnormalities in triad structure, occur more coincident with muscle weakness in the mouse. In total, we provide a comprehensive longitudinal assessment of molecular and structural features of the murine XLMTM disease process.

Intrahepatic Cholestasis Is a Clinically Significant Feature Associated with Natural History of X-Linked Myotubular Myopathy (XLMTM): A Case Series and Biopsy Report

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by profound skeletal muscle weakness, respiratory distress, and motor dysfunction. However, pathology is not limited to muscle and can be associated with life-threatening hepatic peliosis. Hepatobiliary disease has been reported in up to 17% of XLMTM patients but has not been extensively characterized. We report on five XLMTM patients who experienced intrahepatic cholestasis in their disease natural history, illustrating the need to further investigate these manifestations. These patients shared presentations that included pruritus, hypertransaminemia, and hyperbilirubinemia with normal gamma-glutamyl transferase, following infection or vaccination. Three patients who had genetic testing showed no evidence of genetic mutations associated with familial cholestasis. In one patient, progression to cirrhotic, decompensated liver disease occurred. Further investigations into the molecular pathomechanism underpinning these clinical observations in XLMTM patients will be important for informing patient care.

Estimation of the Quality-of-Life Impact of X-Linked Myotubular Myopathy

X-linked myotubular myopathy (XLMTM) is a rare, severe, neuromuscular disorder for which novel treatments are under investigation. This study estimated quality-of-life weights (or utilities) for children with XLMTM. The state that was rated the worst described a child unable to sit and requiring invasive ventilation for≥16 hours a day (utility = –0.07 or –0.27 depending on method used). The state describing a child who can stand and walk and does not require invasive ventilation was the most highly rated state and had a utility of 0.91 or 0.77 (depending on method used). Nine health state vignettes were developed for XLMTM defined in terms of respiratory and motor function based on clinical trial data from parents completing the Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) Domain 1 scale assessing mobility, transfers, sitting, playing, eating, grooming and dressing. These data were supplemented with qualitative data from parent interviews on the daily impact of XLMTM, especially in terms of psychological wellbeing, pain and discomfort, and communication. Seven clinical experts reviewed the draft vignettes for accuracy. Vignettes were rated by members of the UK general public using a time trade-off (TTO) interview and an EQ-5D-5L assessment. This study demonstrated a substantial impact of XLMTM on utility weights.

X-Linked Myotubular Myopathy: A Novel Mutation Expanding the Genotypic Spectrum of a Phenotypically Heterogeneous Myopathy

X-linked myotubular myopathy (XLMTM), a centronuclear congenital myopathy secondary to pathogenic variants in the MTM1 gene encoding myotubularin, is typically recognized for its classic and severe phenotype which includes neonatal hypotonia, severe muscle weakness, long-term ventilator dependence, markedly delayed gross motor milestones with inability to independently ambulate, and a high neonatal and childhood mortality. However, milder congenital forms of the condition and other phenotypes are recognized. We describe a 6-year-old boy with a mild XLMTM phenotype with independent gait and no respiratory insufficiency even in the neonatal period. The child has a hemizygous novel splice site variant in the MTM1 gene (c.232–25A > T) whose pathogenicity was confirmed by cDNA studies (exon 5 skipping) and muscle biopsy findings. We also compared the phenotype of our patient with the few reported cases that presented a mild XLMTM phenotype and no respiratory distress at birth, and discussed the potential mechanisms underlying this phenotype such as the presence of residual expression of the normal myotubularin transcript.