Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies Stephanie A. Robb a,⇑ , Caroline A. Sewry a,d , James J. Dowling e , Lucy Feng a , Tom Cullup f , Sue Lillis f , Stephen Abbs f , Melissa M. Lees b , Jocelyn Laporte g , Adnan Y. Manzur a , Ravi K. Knight h , Kerry R. Mills j , Michael G. Pike i , Wolfram Kress k , David Beeson l , Heinz Jungbluth j,m , Matthew C. Pitt c , Francesco Muntoni a a The Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, London, UK b Department of Clinical Genetics, Institute of Child Health and Great Ormond Street Hospital, London, UK c Department of Neurophysiology, Institute of Child Health and Great Ormond Street Hospital, London, UK d Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK e Division of Pediatric Neurology, University of Michigan, Ann Arbor, MI, USA f DNA Laboratory, GSTS Pathology, Guy’s Hospital, London, UK g Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch F-67400, France h Department of Neurophysiology, Oxford Childrens’ Hospital, Oxford, UK i Department of Paediatric Neurology, Oxford Childrens’ Hospital, Oxford, UK j Clinical Neuroscience Division, King’s College, London, UK k Institut fu ¨ r Humangenetik, Biozentrum, Am Hubland, Wu ¨ rzburg, Germany l Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK m Department of Paediatric Neurology – Neuromuscular Service, Evelina Children’s Hospital, London, UK Received 4 November 2010; received in revised form 1 February 2011; accepted 9 February 2011 Abstract Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally sug- gested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation. Ó 2011 Elsevier B.V. All rights reserved. Keywords: Congenital myasthenic syndromes; Centronuclear myopathy; Neuromuscular junction; Acetylcholinesterase inhibitors 1. Introduction The centronuclear myopathies are genetically heteroge- neous and characterised by prominent, centrally located 0960-8966/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2011.02.012 ⇑ Corresponding author. Address: Dubowitz Neuromuscular Centre, 10th floor, Nurses Home, Great Ormond Street Hospital for Children, London WC1N 3JH, UK. Tel.: +44 (0) 207 405 9200x0632; fax: +44 (0) 20 7829 7923. E-mail address: robbs@gosh.nhs.uk (S.A. Robb). www.elsevier.com/locate/nmd Available online at www.sciencedirect.com Neuromuscular Disorders xxx (2011) xxx–xxx ARTICLE IN PRESS Please cite this article in press as: Robb SA et al., Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies, Neuromuscul Disord (2011), doi:10.1016/j.nmd.2011.02.012