Extensive morphological and immunohistochemical characterization in myotubular myopathy

Abstract

The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM1-mutations according to the "adjusted-age" at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers. The X-linked neonatal form of myotubular myopathy is the most severe form of centronuclear myopathy. The disease is caused by mutations in the MTM1 gene encoding myotubularin. The severe neonatal form is characterised by hypotonia, muscle weakness, hypotrophy and respiratory failure requiring assisted ventilation immediately after birth. In this study, we perform a re-evaluation of morphological changes in skeletal muscle biopsies. We demonstrated that there are not a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibres without any increase in the number of satellite cells, associated with a marked disorganisation of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibres. © 2013 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.