Myasthenia and related disorders of the neuromuscular junction

Spillane, Jennifer; Beeson, David; Kullmann, Dimitri M.

doi:10.1136/jnnp.2008.169367

Cited by 47 publications

(32 citation statements)

References 113 publications

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“…The NMJ has been confirmed to be the main target of several autoimmune diseases, caused by antibodies to pre-or postsynaptic proteins. It has been shown that interference with MuSK synthesis can cause declustering of AChRs; however, the pathogenicity of anti-MuSK antibodies, although confirmed by passive transfer experiments, is poorly understood [34]. Our data suggest that the morphological evidence of mitochondrial dysfunction would support the notion of alterations in muscle mitochondria contributing to both NMJ pathology, and muscle atrophy and weakness.…”

Section: Discussionsupporting

confidence: 49%

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: Discussionsupporting

confidence: 49%

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

et al. 2010

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“…In this context of atrophic features, the beneficial effect of ephedrine and salbutamol on patients with myasthenia with AChE deficiency becomes more understandable (17, 60, 61). These 2 drugs are β2‐adrenergic receptor agonists that have been shown to promote muscle growth and strength (62, 63).…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ‐deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency

et al. 2016

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The collagen ColQ anchors acetylcholinesterase (AChE) in the synaptic cleft of the neuromuscular junction (NMJ). It also binds MuSK and perlecan/dystroglycan, 2 signaling platforms of the postsynaptic domain. Mutations in ColQ cause a congenital myasthenic syndrome (CMS) with AChE deficiency. Because the absence of AChE does not fully explain the complexity of the syndrome and there is no curative treatment for the disease, we explored additional potential targets of ColQ by conducting a large genetic screening of ColQ-deficient mice, a model for CMS with AChE deficiency, and analyzed their NMJ and muscle phenotypes. We demonstrated that ColQ controls the development and the maturation of the postsynaptic domain by regulating synaptic gene expression. Notably, ColQ deficiency leads to an up-regulation of the 5 subunits of the nicotinic acetylcholine receptor (AChR), leading to mixed mature and immature AChRs at the NMJ of adult mice. ColQ also regulates the expression of extracellular matrix (ECM) components. However, whereas the ECM mRNAs were down-regulated in vitro, compensation seemed to occur in vivo to maintain normal levels of these mRNAs. Finally, ColQ deficiency leads to a general atrophic phenotype and hypoplasia that affect fast muscles. This study points to new specific hallmarks for this CMS.-Sigoillot, S.

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“…Sera from healthy controls (HC), matched for age and sex, were collected at Uppsala University Hospital transfusion unit, Sweden. Diagnostic criteria of MG included objective muscle fatigue and neurophysiological evidence of disturbed neuromuscular transmission (decrement on repetitive nerve stimulation and/or increased jitter on single fibre electromyography), further supported by detection of AChR antibodies14. Clinical classification of MG status according to the Myasthenia Gravis Foundation of America (MGFA)15 included only ocular weakness (MGFA class I) and generalized weakness of mild (MGFA class II), moderate (MGFA class III) or severe (MGFA class IV) degree predominantly affecting limb or axial muscles (subtype A) or bulbar muscles (subtype B).…”

Section: Methodsmentioning

confidence: 99%

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

Molin

Westerberg

Punga

2017

Sci Rep

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This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

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Myasthenia and related disorders of the neuromuscular junction

Cited by 47 publications

References 113 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

Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ‐deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

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