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From the Institute for Neuroscience and Muscle Research (G.L.O., M.Y., N.P., H.A.B., T.B.D., K.N.N., N.F.C., S.T.C.), Kids Research Institute, T.Y. Department of Neurology (M.M., R.W.), and Heart Centre for Children (C.T.), Children's Hospital at Westmead, Sydney; Discipline of Paediatrics and Child Health (G.L.O., M.M., H.A.B., K.N.N., N.F.C., S.T.C.), Faculty of Medicine, University of Sydney, Australia; Departments of Genetics (C.V.) and Child Neurology (J.M.F.), University of Groningen University Medical Center Groningen, the Netherlands; Analytic and Translational Genetics Unit (M.L., D.G.M.), Massachusetts General Hospital, Boston; Broad Institute of Harvard and Massachusetts Institute of Technology (M.L., D.G.M.), Cambridge; Department of Neurology (A.G.E.), Mayo Clinic, Rochester, MN; Murdoch Children's Research Institute (K.N.N.), Royal Children's Hospital, Victoria, Australia; and Department of Human Genetics (E.-J.K.), Radboud University Medical Center, Nijmegen, the Netherlands.
Published: October 2016
AI Article Synopsis
Article Abstract
Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3.
Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing.
Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures.
Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.
