Lambert–Eaton myasthenic syndrome: mouse passive‐transfer model illuminates disease pathology and facilitates testing therapeutic leads

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP.

Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

“…In Drosophila melanogaster , voltage-gated shaker (K v ) channels were shown to be up-regulated following knockout of BK channels, such that block of K v channels with 4-aminopyridine caused a large increase in transmitter release at the NMJ ( Lee et al, 2008 ; see, however, Warbington et al, 1996 ). This treatment is thought to increase Ca 2+ entry and vesicle release because the block of K v channels widens the presynaptic action potential ( Wang et al, 2016 ; Meriney et al, 2018 ; Ng et al, 2017 ). We tested the effect of the K v channel blocker 3,4-DAP in WT and BK −/− NMJs ( Fig.…”

An Extensive-stage Small-cell Lung Cancer Case With Preexisting Lambert-Eaton Myasthenic Syndrome Successfully Treated With an Immune Checkpoint Inhibitor

“…Tumor cells in SCLC have a neuroendocrine origin and express the same types of VGCCs as nerve terminals, therefore the immune system develops antibodies against these cancer proteins and misdirects against the nervous system. 4 A preclinical study emphasized the potential of ICIs to enhance and misdirect spontaneously occurring antitumor immune responses against the nervous system, thus causing PNSs. 5 Furthermore, some case reports showed that LEMS developed as a potential neurological irAE in patients treated with ICIs.…”

Lambert-Eaton Myasthenic Syndrome and Botulism

“…This then impairs ACh vesicle release through a variety of mechanisms that affect the active zone of a neuromuscular junction: downregulation of presynaptic P/Q-type VGCCs, disorganization of vesicle release sites, and upregulation of alternative calcium channels. 2,3 Variable release of ACh results in failure of neuromuscular transmission, manifesting as weakness, autonomic dysfunction, or both. LEMS can occur as a paraneoplastic syndrome associated with malignancy (cancer-associated LEMS) or as an autoimmune phenomenon in the absence of malignancy (nontumor LEMS).…”

“…LEMS is a presynaptic disorder characterized by the dysfunctional release of ACh vesicles at the neuromuscular junction due to the presence of antibodies to the pore-forming α1A subunit of the P/Q-type VGCC. This then impairs ACh vesicle release through a variety of mechanisms that affect the active zone of a neuromuscular junction: downregulation of presynaptic P/Q-type VGCCs, disorganization of vesicle release sites, and upregulation of alternative calcium channels 2,3 . Variable release of ACh results in failure of neuromuscular transmission, manifesting as weakness, autonomic dysfunction, or both.…”