Roger G Whittaker1, David N Herrmann2, Boglarka Bansagi2, Bashar Awwad Shiekh Hasan2, Robert Muni Lofra2, Eric L Logigian2, Janet E Sowden2, Jorge L Almodovar2, J Troy Littleton2, Stephan Zuchner2, Rita Horvath2, Hanns Lochmüller2. 1. From the Institute of Neuroscience (R.G.W., B.A.S.H.) and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., R.M.L., R.H., H.L.), Newcastle University, Newcastle, UK; Department of Neurology (D.N.H., E.L.L., J.E.S.), University of Rochester Medical Center, NY; Department of Neurology (J.L.A.), Dartmouth Hitchcock Clinic, Geisel School of Medicine, Hanover, NH; The Picower Institute for Learning and Memory (J.T.L.), Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA; and Dr. John T. Macdonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, Miami, FL. Roger.whittaker@newcastle.ac.uk. 2. From the Institute of Neuroscience (R.G.W., B.A.S.H.) and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., R.M.L., R.H., H.L.), Newcastle University, Newcastle, UK; Department of Neurology (D.N.H., E.L.L., J.E.S.), University of Rochester Medical Center, NY; Department of Neurology (J.L.A.), Dartmouth Hitchcock Clinic, Geisel School of Medicine, Hanover, NH; The Picower Institute for Learning and Memory (J.T.L.), Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA; and Dr. John T. Macdonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), University of Miami, Miller School of Medicine, Miami, FL.
Abstract
OBJECTIVES: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. METHODS: We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine. RESULTS: Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission. CONCLUSION: SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.
OBJECTIVES: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. METHODS: We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine. RESULTS: Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission. CONCLUSION: SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.
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