Pre‐ and postsynaptic neuromuscular junction abnormalities in musk myasthenia

Niks, Erik H.; Kuks, Jan B. M.; Wokke, John H. J.; Veldman, H.; Bakker, Egbert; Verschuuren, Jan J.; Plomp, Jaap J.

doi:10.1002/mus.21642

Cited by 54 publications

(52 citation statements)

References 26 publications

(43 reference statements)

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“…Ultrastructural studies have previously focused on the description of NMJs, offering controversial results: structural integrity of nerve terminals and junctional folds were found in MuSK-MG, while both degeneration and decreased postsynaptic folds have been described with a shorter distance between the postsynaptic membrane and myofibrillar compartment [16,17,19]. In these cases, mitochondria were localized in the subsynaptic space, accumulating directly beneath the postsynaptic membrane, whereas subsynaptic nuclei disappeared.…”

Section: Discussionmentioning

confidence: 93%

“…The most important mechanism of AChR loss is the complement-mediated damage in the postsynaptic membrane resulting from complement-mediated injury to the endplates with morphological simplification of the postsynaptic folds [16,19]. While MuSK function is essential during the development of the NMJ, its role in the adult muscle is less clear, although it is probably involved in structure maintenance of the postsynaptic membrane [14,17,20]. In addition, it is still not clear how MuSK antibodies cause myasthenic symptoms, and it has even been suggested that they may not be pathogenic [16].…”

Section: Discussionmentioning

confidence: 99%

“…Endplate studies performed on intercostal muscle specimen from a patient with a high titer of anti-MuSK antibodies by transmission electron microscopy (TEM) reported structural integrity of nerve terminals and junctional folds, even if focal myofibrillar degeneration was noted near the endplate region [16]. More recently, both presynaptic and postsynaptic ultrastructural changes in the NMJ of a MuSK-MG patient were described [17]. However, both studies reported only one patient and intercostal muscles may not be the one mainly affected by the disease.…”

Section: Introductionmentioning

confidence: 97%

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Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies

et al. 2010

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Patients with myasthenia gravis (MG) with antibodies to muscle-specific receptor tyrosine kinase (MuSK) differ from acetylcholine receptor (AChR)-positive MG patients, as they frequently present with severe oculobulbar muscle weakness or with neck, shoulder, and respiratory muscle involvement. The neuromuscular junction (NMJ) has been confirmed to be the main target of both AChR- and MuSK-MG. However, histopathological investigation disclosed that muscle fiber atrophy was prevalent in AChR-MG, whereas mild myopathic changes and mitochondrial abnormalities were more frequently observed in MuSK-MG. As the pathogenetic mechanism in MuSK-MG remains unclear, this study investigated the submicroscopic pattern of muscle histopathology to establish a possible correlation between clinical involvement and subcellular morphological findings. Muscle biopsies from seven MuSK-MG patients and from seven patients with AChR-MG were analyzed by transmission electron microscopy. Myopathic and mitochondrial abnormalities were more prominent in MuSK-MG and show giant, swollen, and degenerated mitochondria with fragmented cristae. The most common changes in AChR-MG muscles were fiber atrophy, myofibrillar disarray, and Z-line streaming, consistent with mild neurogenic abnormalities. A different pathogenetic mechanism is emerging in MuSK-MG compared to AChR-MG. Mitochondrial abnormalities seem to be more prominent in MuSK-MG, whereas neurogenic atrophy is observed in AChR-MG.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies

et al. 2010

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“…In vitro microelectrode studies showed a normal EPP decay time constant. 34 In the 3 MuSK-MG patients observed by us, the MEPC decay times were shorter than normal, normal, and 2-fold prolonged 33 compared to controls. Thus, our biopsy findings do not indicate that MuSK-MG patients have endplate AChE deficiency.…”

Section: In Vitro Plate-binding Assay Shows That Musk-igg Blocks Bindmentioning

confidence: 62%

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

Kawakami¹,

Ito²,

Hirayama³

et al. 2011

Neurology

111

125

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Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%-15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK-immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods:We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of ColqϪ/Ϫ mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice.

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“…Studies have shown alterations in nAChR expression in some conditions including muscle denervation (Roztler and Brenner 1990;Schuetze and Role 1987;Gattenlöhner et al 2002), nerve injury (Ma et al 2007), alterations muscle fiber type composition (Jin et al 2008), relative muscle activity (Roztler and Brenner 1990) and some pathologies such myasthenia gravis and congenital myasthenic syndromes (Kalamida et al 2007). According to Niks et al (2010) abnormalities in the proteins of the dystrophinglycoprotein complex can also influence the NMJ structure changing the functional properties nAChRs modulating the skeletal muscle phenotype (Jin et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Morphological aspects of neuromuscular junctions and gene expression of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle of rats with heart failure

et al. 2011

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HF is syndrome initiated by a reduction in cardiac function and it is characterized by the activation of compensatory mechanisms. Muscular fatigue and dyspnoea are the more common symptoms in HF; these may be due in part to specific skeletal muscle myopathy characterized by reduced oxidative capacity, a shift from slow fatigue resistant type I to fast less fatigue resistant type II fibers and downregulation of myogenic regulatory factors (MRFs) gene expression that can regulate gene expression of nicotinic acetylcholine receptors (nAChRs). In chronic heart failure, skeletal muscle phenotypic changes could influence the maintenance of the neuromuscular junction morphology and nAChRs gene expression during this syndrome. Two groups of rats were studied: control (CT) and Heart Failure (HF), induced by a single intraperitoneal injection of monocrotaline (MCT). At the end of the experiment, HF was evaluated by clinical signs and animals were sacrificed. Soleus (SOL) muscles were removed and processed for morphological, morphometric and molecular NMJ analyses. Our major finding was an up-regulation in the gene expression of the alpha1 and epsilon subunits of nAChR and a spot pattern of nAChR in SOL skeletal muscle in this acute monocrotaline induced HF. Our results suggest a remodeling of nAChR alpha1 and epsilon subunit during heart failure and may provide valuable information for understanding the skeletal muscle myopathy that occurs during this syndrome.

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Pre‐ and postsynaptic neuromuscular junction abnormalities in musk myasthenia

Cited by 54 publications

References 26 publications

Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies

Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

Morphological aspects of neuromuscular junctions and gene expression of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle of rats with heart failure

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