Two novel mutations in the COLQ gene cause endplate acetylcholinesterase deficiency.

Congenital myasthenic syndromes with endplate acetylcholinesterase deficiency are very rare autosomal recessive diseases, characterized by onset of the disease in childhood, general weakness increased by exertion, ophthalmoplegia and refractoriness to anticholinesterase drugs. To date, all reported cases are due to mutations within the gene encoding ColQ, a specific collagen that anchors acetylcholinesterase in the basal lamina at the neuromuscular junction. We identified two new cases of congenital myasthenic syndromes with endplate acetylcholinesterase deficiency. The two patients showed different phenotypes. The first patient had mild symptoms in childhood, which worsened at 46 years with severe respiratory insufficiency. The second patient had severe symptoms from birth but improved during adolescence. In both cases, the absence of acetylcholinesterase was demonstrated by morphological and biochemical analyses, and heteroallelic mutations in the COLQ gene were found. Both patients presented a novel splicing mutation (IVS1-1G-->A) affecting the exon encoding the proline-rich attachment domain (PRAD), which interacts with acetylcholinesterase. This splicing mutation was associated with two different mutations, both of which cause truncation of the collagen domain (a known 788insC mutation belonging to one patient and a novel R236X to the other) and may impair its trimeric organization. The close similarity of the mutations of these two patients with different phenotypes suggests that other factors may modify the severity of this disease.