Brain Advance Access originally published online on January 7, 2008
Brain 2008 131(3):747-759; doi:10.1093/brain/awm325
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Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes
1Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany, 2Servicio de Neurologia, Hospital Universitari La Fe, Valencia, Spain, 3Division of Pediatric Neurology, College of Medicine, 4Division of Neurophysiology, Department of Neurosciences, Armed Forces Hospital, Riyadh, Saudi Arabia, 5Laboratory of Molecular Medicine, Bambino Gesu Children's Hospital, Rome, Italy, 6Children's Hospital, University of Bonn, 7Department of Neuropediatrics, Universitäts-Kinderklinik Münster, Germany, 8Clinic for Child Neurology and Psychiatry, Medical University Belgrade, Serbia, 9Department of Pediatric Neurology, University Hospital ‘Thomayerova’, Prague, Czech Republic, 10Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Déu, Esplugues (Barcelona), Spain, 11Department of Neurology, Bethesda Children's Hospital, Budapest, Hungary, 12University Children's Hospital, Bratislava, Slovakia, 13Department of Neuropediatrics, Medical Faculty of the Charite, Humboldt University, Berlin, Germany, 14Neuromuscular/Neurology Division, Hospital de Clinicas, Universidade Federal do Parana, Curitiba, Brazil and 15Department of Pediatric Neurology, University of Essen, Germany
Correspondence to: Hanns Lochmüller, MD, Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK E-mail: hanns.lochmuller{at}ncl.ac.uk
Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the ‘classical’ phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.
Key Words: congenital myasthenic syndromes; COLQ; acetylcholinesterase; esterase inhibitors
Abbreviations: AChE, acetylcholinesterase; CMAP, compound muscle action potential; CMS, congenital myasthenic syndromes; LGM, limb-girdle myasthenia; PRAD, proline-rich region attachment domain; RNS, repetitive nerve stimulation; RSV, respiratory syncytial virus; SC-CMS, slow-channel CMS
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Received July 19, 2007. Revised December 3, 2007. Accepted December 12, 2007.
*Present address: Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
These authors contributed equally to this work.