Pre- and postsynaptic neuromuscular junction abnormalities in musk myasthenia

Department of Neurology, Leiden University Medical Center, K5Q-114, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Muscle & Nerve (Impact Factor: 2.31). 08/2010; DOI: 10.1002/mus.21642
Source: OAI

ABSTRACT Autoantibodies to muscle-specific kinase (MuSK) can cause myasthenia gravis (MG). The pathophysiological mechanism remains unknown. We report in vitro electrophysiological and histological studies of the neuromuscular junction in a MuSK MG patient. Low levels of presynaptic acetylcholine release and small miniature endplate potentials were found. This combination of pre- and postsynaptic abnormalities was supported by histology, revealing partially denervated postsynaptic areas, and some degeneration of postsynaptic folds. Results suggest that anti-MuSK antibodies reduce the stability of muscle-nerve contact.

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    ABSTRACT: The presence of autoantibodies against muscle-specific kinase (MuSK) at the neuromuscular junction (NMJ) results in myasthenia gravis (MG). MuSK antibody-associated MG (MuSK MG) patients often have severe symptoms, including bulbar dysfunction, respiratory insufficiency and atrophy of the facial and tongue muscles. MuSK antibodies in MG patients predominantly belong to the IgG4 subclass, and the unique properties of IgG4 antibodies are directly associated with the pathogenic mechanisms of MuSK MG. Histopathological studies inanimal models of MuSK MGhave revealedthat anti-MuSK antibodies cause contraction of motor terminals,significant loss of acetylcholine receptor (AChR) expression, and a reduction in synaptic folds at the postsynaptic membrane in the absence of complement involvement. Failure of neuromuscular transmission at pre- and postsynaptic membranes of the NMJs has been observedin both patients and animal models of MuSK MG. A murine model of MuSK-MG revealed the mechanisms underlying cholinergic hypersensitivity after administration of acetylcholinesterase inhibitors, which has also been observed in MuSK-MG patients. Further studies of this model have provided evidence suggesting that 3,4-diaminopyridine may be effective as a symptomatic therapy for MuSK MG.
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    ABSTRACT: MuSK myasthenia gravis is a rare, severe autoimmune disease of the neuromuscular junction, only identified in 2001, with unclear pathogenic mechanisms. In this review we describe the clinical aspects that distinguish MuSK MG from AChR MG, review what is known about the role of MuSK in the development and function of the neuromuscular junction, and discuss the data that address how the antibodies to MuSK lead to neuromuscular transmission failure.
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    ABSTRACT: Autoantibodies against three different postsynaptic antigens and one presynaptic antigen at the neuromuscular junction are known to cause myasthenic syndromes. The mechanisms by which these antibodies cause muscle weakness varies from antigenic modulation and complement-mediated membrane damage to inhibition of endogenous ligand binding and blocking of essential protein-protein interactions. These mechanisms are related to the autoantibody titre, specific epitopes on the target proteins and IgG autoantibody subclass. We here review the role of specific autoantibody-binding epitopes in myasthenia gravis, their possible relevance to the pathophysiology of the disease, and potential implications of epitope mapping knowledge for new therapeutic strategies. This article is protected by copyright. All rights reserved.
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Erik H Niks