Centronuclear myopathies (CNM) are a group of congenital myopathies classically defined by the presence of an abnormally high number of muscle fibres with nuclei organised in rows in the central part of the fibre. Over recent years there have been important advances in the knowledge of the genetic bases of the three main forms of CNM: the X-linked recessive form or myotubular myopathy (XLMTM) with severe neonatal phenotype, caused by mutations in the MTM1 gene; the classical autosomal dominant forms with mild, moderate or severe phenotypes caused by mutations in the DNM2 gene; and an autosomal recessive form presenting severe and moderate phenotypes caused by mutations in the BIN1 gene. Although at present the histopathological distinction between these described forms of CNM seems well established, these three genes do not explain all the cases of CNM and there still exist an important number of genetically unresolved cases with prominent myonuclei internalisation and centralisation. This mini-review lays emphasis on the particular histopathological abnormalities associated with specific gene mutations, the high significance of establishing a distinction between nuclear centralisation (i.e. the presence of one nucleus at the geometric centre of the fibre) and nuclear internalisation (i.e. one or more nuclei anywhere inside the sarcoplasm) for CNM categorisation, and demonstrates how additional structural alterations within muscle fibres are a useful criterion for suggesting or discarding DNM2-, BIN1- or MTM1-related CNM.
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