Pediatr Neurol 2014 Jul 22;51(1):165-9. Epub 2014 Mar 22.
Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates. Electronic address:
Background: Congenital myasthenic syndromes with end-plate acetylcholinesterase deficiency are rare autosomal recessive disorders characterized by onset of the disease in early childhood, general weakness exacerbated by exertion, ophthalmoplegia, and refractoriness to anticholinesterase drugs. To date, all reported cases have been attributed to mutations in 18 genes including the COLQ gene that encodes a specific collagen that anchors acetylcholinesterase at the basal lamina of the neuromuscular junction. We identified a Syrian family with two children of consanguineous parents from two branches affected with congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency.
Method: The absence of acetylcholinesterase antibodies was demonstrated biochemically. Consequently, all the coding regions, exon-intron boundaries, and the 5' and 3' untranslated regions of the COLQ gene were amplified and sequenced using the Sanger sequencing method.
Results: We observed that the severity of the phenotype in the two affected children differed. One child had mild symptoms that included difficulties in gait and feeding with mild respiratory insufficiency. Her sibling died in the first months of life because of severe respiratory failure. The second patient had severe symptoms from birth and has been mechanically ventilated. DNA sequencing revealed a novel homozygous single nucleotide substitution mutation (c.1010T>C) in the COLQ gene in both patients. This substitution leads to a missense amino acid substitution at position 337 of the protein (p.Ile337Thr). This mutation is likely to impair ColQ's trimeric organization and therefore its anchoring within the synaptic basal lamina.
Conclusion: We identified the molecular cause underlying congenital myasthenic syndrome in two patients. The marked phenotypic variation suggests that other factors including modifier genes may affect the severity of this disease.