title: Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes.
abstract: 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.
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Violeta
authors.initials: V
authors.lastname: Mihaylova
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Vilchez
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Kabiraj
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Joachim
authors.initials: J
authors.lastname: Wölfle
authors.forename: Felix
authors.initials: F
authors.lastname: Schreiner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kurlemann
authors.forename: Vedrana Milic
authors.initials: VM
authors.lastname: Rasic
authors.forename: Dana
authors.initials: D
authors.lastname: Siskova
authors.forename: Jaume
authors.initials: J
authors.lastname: Colomer
authors.forename: Agnes
authors.initials: A
authors.lastname: Herczegfalvi
authors.forename: Katarina
authors.initials: K
authors.lastname: Fabriciova
authors.forename: Bernhard
authors.initials: B
authors.lastname: Weschke
authors.forename: Rosana
authors.initials: R
authors.lastname: Scola
authors.forename: Friederike
authors.initials: F
authors.lastname: Hoellen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D000110:Acetylcholinesterase / Q000172:deficiency / Q000235:genetics*; D000200:Action Potentials; D000293:Adolescent; D017668:Age of Onset; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000235:genetics*; D004558:Electric Stimulation; D005133:Eye Movements; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009124:Muscle Proteins; D003094:Collagen; D000110:Acetylcholinesterase; C114027:COLQ protein, human