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1. Introduction and overviewSixteen clinicians and basic scientists from 4 countriesconvened from the 31st of May to the 2nd of June 2013 inNaarden, The Netherlands, for the 198th ENMC sponsoredWorkshop on Centronuclear/Myotubular myopathies(CNM/MTM). The workshop was also attended by AnneLennox and Melanie Spring as representatives of theMyotubular Trust, a European patient support group forpatients affected by myotubular (centronuclear) myopathies,and by Hal Landy, Deborah Ramsdell and MatthewPatterson, representatives of 2 industry partners, Valerionand Audentes Therapeutics, with an interest in developingspecific therapies for CNM/MTM.Following a welcome from Daniel Zollinger, ENMCrepresentative, and the chairpersons of the workshop,Carina Wallgren-Pettersson (Helsinki, Finland) andJocelyn Laporte (Illkirch, France) gave an overview ofnew developments in the field: Since the most recent, 6thENMC MTM/CNM workshop held in January 2009 [1],further in-depth phenotypical characterization has lead tothe proposal of histopathological subclasses [2], wideningof the clinical spectrum for genetically already resolvedforms [3–5] and refinement of the molecular diagnosis[6,7]. Mutations in the skeletal muscle ryanodine receptor(RYR1) gene [8–10] and the CCDC78 gene [11] have nowbeen associated with congenital myopathies withprominent internal nuclei and the arrival of nextgeneration sequencing for genetic diagnosis has lead tothe identification of further novel genes [11]. Models tostudy and/or to rescue the affected cellular pathways arenow available in yeast [12,13], Caenorhabditis elegans [14–16], drosophila [17], zebrafish [18,19], mouse [20–23] anddog [24]. Those models have suggested several potentialpathogenic mechanisms, including alteration of triads andcalcium handling [18,25], defects of the neuromuscularjunction [19,26,27], satellite cells [28], mitochondria andthe desmin cytoskeleton [29], as well as the autophagypathway [23,30]. Some of those pathogenic mechanismsare common to different forms of CNM [31,32]. Severalproof-of-concept studies aimed at amelioration of theCNM phenotypes have recently been reported, includingreplacement of the myotubularin protein through either

X-linked myotubular myopathy is a severe congenital myopathy that presents in the neonatal period with profound hypotonia and an inability to establish spontaneous respiration. Usually death occurs in infancy from respiratory failure. However, there is phenotypic variability; a number of affected boys have achieved respiratory independence and become ambulatory. Disease-causing mutations have been identified throughout the MTM1 gene on Xq28. MTM1 encodes the protein myotubularin, which is expressed ubiquitously. The main objectives of this study were to establish whether the nature or site of the mutation in the MTM1 gene could predict severity of the disease and to investigate whether early intensive clinical intervention facilitated survival until spontaneous improvement occurred. An association was demonstrated between the presence of a non-truncating mutation of the MTM1 gene and the mild phenotype. However, many non-truncating mutations were also seen in association with the severe phenotype and these were not confined to recognized functional domains of the protein. This suggests that the use of mutation analysis to predict prognosis in the early period following diagnosis is limited. Unexpectedly, over 50 patients surviving for more than 1 year were identified in this study. Further information obtained on 40 of these cases revealed that 50% were receiving 24-h ventilatory support, while 27% were ventilated at night only. The high survival rate for this disorder therefore reflects intensive medical intervention without which the majority of these boys would not survive.