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December 01, 2015; 85 (22) Article

Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome

Roger G. Whittaker, David N. Herrmann, Boglarka Bansagi, Bashar Awwad Shiekh Hasan, Robert Muni Lofra, Eric L. Logigian, Janet E. Sowden, Jorge L. Almodovar, J. Troy Littleton, Stephan Zuchner, Rita Horvath, Hanns Lochmüller
First published October 30, 2015, DOI: https://doi.org/10.1212/WNL.0000000000002185
Roger G. Whittaker
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.
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David N. Herrmann
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.
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Boglarka Bansagi
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.
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Bashar Awwad Shiekh Hasan
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.
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Robert Muni Lofra
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.
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Eric L. Logigian
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.
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Janet E. Sowden
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.
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Jorge L. Almodovar
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.
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J. Troy Littleton
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.
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Stephan Zuchner
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.
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Rita Horvath
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.
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Hanns Lochmüller
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.
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Citation
Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome
Roger G. Whittaker, David N. Herrmann, Boglarka Bansagi, Bashar Awwad Shiekh Hasan, Robert Muni Lofra, Eric L. Logigian, Janet E. Sowden, Jorge L. Almodovar, J. Troy Littleton, Stephan Zuchner, Rita Horvath, Hanns Lochmüller
Neurology Dec 2015, 85 (22) 1964-1971; DOI: 10.1212/WNL.0000000000002185

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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.

GLOSSARY

APB=
abductor pollicis brevis;
CMAP=
compound muscle action potential;
CMS=
congenital myasthenic syndrome;
CMSS=
Congenital Myasthenic Syndrome Scale;
3,4-DAP=
3,4-diaminopyridine;
LEMS=
Lambert-Eaton myasthenic syndrome;
MRC=
Medical Research Council;
MVC=
maximum voluntary contraction;
RNS=
repetitive nerve stimulation;
SYT2=
synaptotagmin II;
TA=
tibialis anterior;
VGCC=
voltage-gated calcium channel

Footnotes

  • ↵* These authors contributed equally to this work.

  • ↵‡ These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received June 10, 2015.
  • Accepted in final form August 6, 2015.
  • © 2015 American Academy of Neurology
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