DOK7 congenital myasthenic syndrome in childhood: Early diagnostic clues in 23 children Andrea Klein a,b,⇑ , Matthew C. Pitt c , John C. McHugh d , Erik H. Niks e , Caroline A. Sewry b,f , Rahul Phadke b , Lucy Feng b , Adnan Y. Manzur b , Sandya Tirupathi g , Catherine DeVile h , Sandeep Jayawant i , Sarah Finlayson j , Jacqueline Palace j , Francesco Muntoni b , David Beeson k , Stephanie A. Robb b a Department of Paediatric Neurology, University Children’s Hospital, Zurich, Switzerland b Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, London, UK c Department of Clinical Neurophysiology, Great Ormond Street Hospital, London, UK d Department of Clinical Neurophysiology, St. Vincent’s University Hospital, Dublin 4, Ireland e Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands f Centre for Inherited Neuromuscular Diseases, RJAH Orthopaedic Hospital, Oswestry, UK g Department of Paediatric Neurology, Belfast City Hospital, UK h Department of Neurology, Great Ormond Street Hospital, London, UK i Department of Paediatric Neurology, Oxford Children’s Hospital, Oxford, UK j Department of Neurology, John Radcliffe Hospital, Oxford, UK k Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK Received 29 January 2013; received in revised form 24 May 2013; accepted 5 June 2013 Abstract Mutations in DOK7 are a common cause of congenital myasthenia. Treatment with ephedrine or salbutamol is effective, but diagnosis is often delayed. The aim of our study was to find early clues to the diagnosis of DOK7 congenital myasthenic syndrome. We included 23 children of 20 families. Onset of symptoms ranged from birth to age 3 years. 13 presented at birth with feeding difficulties, 11 with stridor (documented vocal cord palsy in 7), 3/11 with hypotonia/poor head control. Weakness was more pronounced proximally in all, axial in early presenting infants. Muscle biopsy showed non-specific features in 15/16, type 1 fibre predominance in 14/16, areas devoid of oxidative enzyme activity in 7/16. Muscle imaging was normal in 8/10, 2/10 showed mild non-specific changes. A diagnostic clue suggesting CMS rather than myopathy was the discrepancy between muscle imaging or histology findings compared with the degree of weakness. Repetitive nerve stimulation and stimulation single fibre electromyography were pathological in 9/17 and 13/14, respectively. In conclusion, stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy point to the diagnosis and should lead to neurophysiological and genetic investigation. Fatigability can be absent or easily missed in the first years of life. Ó 2013 Elsevier B.V. All rights reserved. Keywords: Congential myasthenic syndrome; DOK7; Clinical features in childhood 1. Introduction Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by mutations in genes encoding for proteins involved in the neuromuscular junction that lead to an impaired signal transduction. All 0960-8966/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.nmd.2013.06.002 ⇑ Corresponding author at: Department of Paediatric Neurology, University Children’s Hospital, Zurich, Switzerland. Tel.: +41 442667330; fax: +41 44 2667163. E-mail addresses: andrea.klein@kispi.uzh.ch, andreakatharina@ gmx.ch (A. Klein). www.elsevier.com/locate/nmd Available online at www.sciencedirect.com Neuromuscular Disorders 23 (2013) 883–891