Brain Advance Access originally published online on April 17, 2007
Brain 2007 130(6):1497-1506; doi:10.1093/brain/awm068
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Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes
1Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany, 2Department of Neurology, Bethesda Children's Hospital, Budapest, Hungary, 3Servicio de Neurologia, Hospital Universitari La Fe, Valencia, Spain, 4Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Déu, Esplugues (Barcelona), Spain, 5Department of Cancer Genetics, Unit 1010, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 6Hospital de Criancas Maria Pia, Porto, Portugal, 7Department of Neuropediatrics; Staedtische Kliniken, Neuss, Germany, 8Department of Neurology, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany, 9Departments of Neurology/Neurosurgery & Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada, 10Department of Neuropediatrics, Hospital D. Estefania, Lisbon, Portugal, 11Department of Medical Genetics, University of Turku and Turku University Hospital, Turku, Finland, 12Department of Pediatric Neurology, Turku University Hospital, Turku, Finland, 13National Center for Public Health, National Institute of Environmental Health, Department of Molecular Genetics and Diagnostics, Budapest, Hungary, 14Children's Hospital, Technical University Dresden, Germany and 15Neurosciences Group, Weatherall Institute of Molecular Medicine, Department of Clinical Neurology, University of Oxford, UK
Corresponding to: Hanns Lochmüller, MD, Friedrich-Baur-Institute, Molecular Myology Lab, Marchioninistrasse 17, 81377 München, Germany E-mail: hanns.lochmueller{at}med.uni-muenchen.de
Dok (‘downstream-of-kinase’) family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic ‘limb-girdle’ pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that ‘limb-girdle myasthenia (LGM) with tubular aggregates’ previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations.
Key Words: congenital myasthenic syndromes; DOK7; neuromuscular junction; limb-girdle myasthenia (LGM)
Abbreviations: AChR, acetylcholine receptor; CMAP, compound muscle action potential; CMS, congenital myasthenic syndromes; DOK7, downstream-of-kinase 7; LGM, limb-girdle myasthenia; MuSK, skeletal muscle receptor tyrosine kinase; NMJ, neuromuscular junction; PH, pleckstrin homology; PTB, phosphotyrosine-binding domain
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Received November 17, 2006. Revised February 21, 2007. Accepted March 12, 2007.
* Present address: Department of Neuropediatrics, Children's University Hospital, University of Essen, Germany
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