Dominant and recessive congenital myasthenic syndromes caused by <i>SYT2</i> mutations

  • Ricardo A. Maselli
    Department of Neurology University of California Davis Sacramento California USA
  • David T. Wei
    Department of Neurology University of California Davis Sacramento California USA
  • Trent S. Hodgson
    Kaiser Permanente Oakland Medical Center Oakland California USA
  • Jacinda B. Sampson
    Department of Neurology Stanford University Palo Alto California USA
  • Jessica Vazquez
    Department of Neurology University of California Davis Sacramento California USA
  • Heather L. Smith
    Department of Pathology The University of Chicago Chicago Illinois USA
  • Peter Pytel
    Department of Pathology The University of Chicago Chicago Illinois USA
  • Michael Ferns
    Department of Anesthesiology University of California Davis Davis California USA

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<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction/Aims</jats:title><jats:p>We studied a patient with a congenital myasthenic syndrome (CMS) caused by a dominant mutation in the synaptotagmin 2 gene <jats:italic>(SYT2)</jats:italic> and compared the clinical features of this patient with those of a previously described patient with a recessive mutation in the same gene.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We performed electrodiagnostic (EDX) studies, genetic studies, muscle biopsy, microelectrode recordings and electron microscopy (EM).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Both patients presented with muscle weakness and bulbar deficits, which were worse in the recessive form. EDX studies showed presynaptic failure, which was more prominent in the recessive form. Microelectrode studies in the dominant form showed a marked reduction of the quantal content, which increased linearly with higher frequencies of nerve stimulation. The MEPP frequencies were normal at rest but increased markedly with higher frequencies of nerve stimulation. The EM demonstrated overdeveloped postsynaptic folding, and abundant endosomes, multivesicular bodies and degenerative lamellar bodies inside small nerve terminals.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>The recessive form of CMS caused by a <jats:italic>SYT2</jats:italic> mutation showed far more severe clinical manifestations than the dominant form. The pathogenesis of the dominant form likely involves a dominant‐negative effect due to disruption of the dual function of synaptotagmin as a Ca<jats:sup>2+</jats:sup>‐sensor and modulator of synaptic vesicle exocytosis.</jats:p></jats:sec>

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