Journal
NEUROLOGY
Volume 85, Issue 22, Pages 1964-1971Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000002185
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Funding
- EPSRC [EP/K028421/1]
- Wellcome Trust [G102037]
- Inherited Neuropathies Consortium Rare Disease Clinical Research Network, National Institute of Neurological Disorders and Stroke [U54NS065712]
- MRC Centre for Neuromuscular Diseases
- NIH [U54NS065712, NS40296, R01NS075764, R01NS072248]
- JPB Foundation
- MDA
- CMT Association
- Medical Research Council (UK) [G1000848]
- European Research Council [309548]
- Medical Research Council UK [G1002274, 98482]
- European Union [305444, 305121]
- EPSRC [EP/K028421/1] Funding Source: UKRI
- MRC [G1002274, G1000848, MR/K000608/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/K028421/1] Funding Source: researchfish
- Medical Research Council [MR/K000608/1, G1002274, G1000848] Funding Source: researchfish
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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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