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Neurol Genet. 2018 Oct 22;4(6):e282. doi: 10.1212/NXG.0000000000000282. eCollection 2018 Dec.

Identification of a new SYT2 variant validates an unusual distal motor neuropathy phenotype.

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Department of Neurology (N.I.M.-C., M.C., C.V., M.A.S.), University of Miami Miller School of Medicine FL; Department of Biology (Z.G., J.T.L.) and Department of Brain and Cognitive Sciences (Z.G., J.T.L.), The Picower Institute for Learning & Memory, Massachusetts Institute of Technology, Cambridge; and Department of Human Genetics (S.C., A.P.R., L.A., S.Z., M.A.S.), Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL.



To report a new SYT2 missense mutation causing distal hereditary motor neuropathy and presynaptic neuromuscular junction (NMJ) transmission dysfunction.


We report a multigenerational family with a new missense mutation, c. 1112T>A (p. Ile371Lys), in the C2B domain of SYT2, describe the clinical and electrophysiologic phenotype associated with this variant, and validate its pathogenicity in a Drosophila model.


Both proband and her mother present a similar clinical phenotype characterized by a slowly progressive, predominantly motor neuropathy and clear evidence of presynaptic NMJ dysfunction on nerve conduction studies. Validation of this new variant was accomplished by characterization of the mutation homologous to the human c. 1112T>A variant in Drosophila, confirming its dominant-negative effect on neurotransmitter release.


This report provides further confirmation of the role of SYT2 in human disease and corroborates the resultant unique clinical phenotype consistent with heriditary distal motor neuropathy. SYT2-related motor neuropathy is a rare disease but should be suspected in patients presenting with a combination of presynaptic NMJ dysfunction (resembling Lambert-Eaton myasthenic syndrome) and a predominantly motor neuropathy, especially in the context of a positive family history.

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