Brain Advance Access originally published online on April 23, 2007
Brain 2007 130(6):1507-1515; doi:10.1093/brain/awm072
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Clinical features of the DOK7 neuromuscular junction synaptopathy
1Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, 2Department of Clinical Neurology, University of Oxford, The Radcliffe Infirmary, Oxford OX2 6HE, UK and 3Department of Cell Regulation, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Corresponding to: David Beeson, Neurosciences Group, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, UK E-mail: dbeeson{at}hammer.imm.ox.ac.uk
Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions (‘synaptopathy’) but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a ‘limb-girdle’ pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from ‘limb-girdle’ myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.
Key Words: congenital myasthenic syndrome; neuromuscular junction; mutations; DOK7; phenotype
Abbreviations: CMS, congenital myasthenic syndrome; MuSK, muscle-specific tyrosine kinase; PH, plecstrin homology domain; PTB, phosphotyrosine binding domain
Received December 8, 2006. Revised March 7, 2007. Accepted March 14, 2007.
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