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Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome

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Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that disrupts the normally reliable neurotransmission at the neuromuscular junction (NMJ). This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca2+ channels involved with neurotransmitter release. With less neurotransmitter release at the NMJ, LEMS patients experience debilitating muscle weakness. The underlying cause of LEMS in slightly more than half of all patients is small cell lung cancer, and cancer therapy is the priority for these patients. In the remaining cases, the cause of LEMS is unknown, and these patients often rely on symptomatic treatment options, as there is no cure. However, current symptomatic treatment options, such as 3,4-diaminopyridine (3,4-DAP), can have significant dose-limiting side effects; thus, additional treatment approaches would benefit LEMS patients. Recent studies introduced a novel Ca2+ channel agonist (GV-58) as a potential therapeutic alternative for LEMS. Additionally, this work has shown that GV-58 and 3,4-DAP interact in a supra-additive manner to completely restore the magnitude of neurotransmitter release at the NMJs of a LEMS mouse model. In this review, we discuss synaptic mechanisms for reliability at the NMJ and how these mechanisms are disrupted in LEMS. We then discuss the current treatment options for LEMS patients, while also considering recent work demonstrating the therapeutic potential of GV-58 alone and in combination with 3,4-DAP.

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Acknowledgments

We thank A.E. Homan for critically reading the manuscript. This work was supported by the ARCS Foundation scholarship (to T.B.T.) and grants from the National Science Foundation (0844604 and 1249546 to S.D.M.), the National Institutes of Health (GM067082 to P.W.), the Muscular Dystrophy Association (295271 to S.D.M.), and the University of Pittsburgh Central Research Development Fund (to S.D.M.).

Conflict of Interest

The authors declare that they have no conflict of interest.

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  1. Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Tyler B. Tarr & Stephen D. Meriney

  2. Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Tyler B. Tarr & Stephen D. Meriney

  3. Department of Chemistry and Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Peter Wipf

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Tarr, T.B., Wipf, P. & Meriney, S.D. Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome. Mol Neurobiol 52, 456–463 (2015). https://doi.org/10.1007/s12035-014-8887-2

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