Neurophysiological characteristics of MuSK antibody positive Myasthenia Gravis mice: Focal denervation and hypersensitivity to acetylcholinesterase inhibitors

Chroni, Elisabeth; Punga, Anna Rostedt

doi:10.1016/j.jns.2011.12.016

Cited by 18 publications

(12 citation statements)

References 27 publications

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“…In addition to SASD MUAPs, prominent abnormal spontaneous activity can be seen on needle EMG in severe presentations of generalized MG and likely relates to functional denervation of the muscle membrane . Similar observations have been reported in muscle specific kinase (MuSK)‐positive MG (in bulbar muscles), distal predominant MG (in distal muscles), Lambert–Eaton myasthenic syndrome, and botulism . Abnormal spontaneous activity may be seen in acute to chronic cases, and it can resolve after treatment.…”

Section: Clinical Features and Diagnostic Studiessupporting

confidence: 73%

Abnormal spontaneous activity on needle electromyography in myasthenia gravis

et al. 2017

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Section: Clinical Features and Diagnostic Studiessupporting

confidence: 73%

Abnormal spontaneous activity on needle electromyography in myasthenia gravis

et al. 2017

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“…Based on these results, the NMJs of MuSK-Ab-positive MG patients are predicted to be deficient in synaptic AChE, which leads to overreaction to AChEIs and the generation of R-CMAPs and a DIP. In a recent experiment the administration of therapeutic doses of neostigmine evoked R-CMAPs in 94% of MuSK-Ab-positive MG mice but in only 22% of MuSK-Ab-negative MG mice 14. Accordingly, our data suggest that R-CMAPs and/or a DIP elicited by the standard dose of AChEI represent an AChE-deficient status at the NMJ in MuSK-Ab-positive MG patients.…”

Section: Discussionsupporting

confidence: 49%

Clinical and Electrophysiologic Responses to Acetylcholinesterase Inhibitors in MuSK-Antibody-Positive Myasthenia Gravis: Evidence for Cholinergic Neuromuscular Hyperactivity

et al. 2014

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Background and PurposePatients with muscle-specific tyrosine kinase (MuSK) antibody (MuSK-Ab)-positive myasthenia gravis (MG) show distinct responses to acetylcholinesterase inhibitors (AChEIs). Although clinical responses to AChEIs in MuSK-Ab MG are reasonably well known, little is known about the electrophysiologic responses to AChEIs. We therefore investigated the clinical and electrophysiologic responses to AChEIs in MuSK-Ab-positive MG patients.MethodsWe retrospectively reviewed the medical records and electrodiagnostic findings of 17 MG patients (10 MuSK-Ab-positive and 7 MuSK-Ab-negative patients) who underwent electrodiagnostic testing before and after a neostigmine test (NT).ResultsThe frequency of intolerance to pyridostigmine bromide (PB) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (50% vs. 0%, respectively; p=0.044), while the maximum tolerable dose of PB was lower in the former (90 mg/day vs. 480 mg/day, p=0.023). The frequency of positive NT results was significantly lower in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (40% vs. 100%, p=0.035), while the nicotinic side effects of neostigmine were more frequent in the former (80% vs. 14.3%, p=0.015). Repetitive compound muscle action potentials (R-CMAPs) developed more frequently after NT in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (90% vs. 14.3%, p=0.004). The frequency of a high-frequency-stimulation-induced decrement-increment pattern (DIP) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (100% vs. 17.7%, p=0.003).ConclusionsThese results suggest that MuSK-Ab-positive MG patients exhibit unique and hyperactive responses to AChEIs. Furthermore, R-CMAP and DIP development on a standard AChEI dose may be a distinct neurophysiologic feature indicative of MuSK-Ab-positive MG.

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“…Rabbits, rats, and mice that were actively immunized with the extracellular domain of MuSK developed MuSK autoantibodies. They showed impairment of neuromuscular transmission associated with loss of postsynaptic AChR and other changes to the NMJ structure Shigemoto et al 2006;Xu et al 2006;Richman et al 2011;Chroni and Punga 2012;Viegas et al 2012;Patel et al 2014;Ulusoy et al 2014). Passive transfer of IgG from MuSK MG patients into mice also caused loss of postsynaptic AChR and synaptic impairments Viegas et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

et al. 2015

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We investigated the influence of postsynaptic tyrosine kinase signaling in a mouse model of muscle‐specific kinase (MuSK) myasthenia gravis (MG). Mice administered repeated daily injections of IgG from MuSK MG patients developed impaired neuromuscular transmission due to progressive loss of acetylcholine receptor (AChR) from the postsynaptic membrane of the neuromuscular junction. In this model, anti‐MuSK‐positive IgG caused a reduction in motor endplate immunolabeling for phosphorylated Src‐Y418 and AChR β‐subunit‐Y390 before any detectable loss of MuSK or AChR from the endplate. Adeno‐associated viral vector (rAAV) encoding MuSK fused to enhanced green fluorescent protein (MuSK‐EGFP) was injected into the tibialis anterior muscle to increase MuSK synthesis. When mice were subsequently challenged with 11 daily injections of IgG from MuSK MG patients, endplates expressing MuSK‐EGFP retained more MuSK and AChR than endplates of contralateral muscles administered empty vector. Recordings of compound muscle action potentials from myasthenic mice revealed less impairment of neuromuscular transmission in muscles that had been injected with rAAV‐MuSK‐EGFP than contralateral muscles (empty rAAV controls). In contrast to the effects of MuSK‐EGFP, forced expression of rapsyn‐EGFP provided no such protection to endplate AChR when mice were subsequently challenged with MuSK MG IgG. In summary, the immediate in vivo effect of MuSK autoantibodies was to suppress MuSK‐dependent tyrosine phosphorylation of proteins in the postsynaptic membrane, while increased MuSK synthesis protected endplates against AChR loss. These results support the hypothesis that reduced MuSK kinase signaling initiates the progressive disassembly of the postsynaptic membrane scaffold in this mouse model of MuSK MG.

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Neurophysiological characteristics of MuSK antibody positive Myasthenia Gravis mice: Focal denervation and hypersensitivity to acetylcholinesterase inhibitors

Cited by 18 publications

References 27 publications

Abnormal spontaneous activity on needle electromyography in myasthenia gravis

Abnormal spontaneous activity on needle electromyography in myasthenia gravis

Clinical and Electrophysiologic Responses to Acetylcholinesterase Inhibitors in MuSK-Antibody-Positive Myasthenia Gravis: Evidence for Cholinergic Neuromuscular Hyperactivity

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis

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