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Journal of Clinical Medicine May 2021Myasthenia gravis (MG) is an autoimmune neurological disorder characterized by defective transmission at the neuromuscular junction. The incidence of the disease is 4.1... (Review)
Review
Myasthenia gravis (MG) is an autoimmune neurological disorder characterized by defective transmission at the neuromuscular junction. The incidence of the disease is 4.1 to 30 cases per million person-years, and the prevalence rate ranges from 150 to 200 cases per million. MG is considered a classic example of antibody-mediated autoimmune disease. Most patients with MG have autoantibodies against the acetylcholine receptors (AChRs). Less commonly identified autoantibodies include those targeted to muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (Lrp4), and agrin. These autoantibodies disrupt cholinergic transmission between nerve terminals and muscle fibers by causing downregulation, destruction, functional blocking of AChRs, or disrupting the clustering of AChRs in the postsynaptic membrane. The core clinical manifestation of MG is fatigable muscle weakness, which may affect ocular, bulbar, respiratory and limb muscles. Clinical manifestations vary according to the type of autoantibody, and whether a thymoma is present.
PubMed: 34064035
DOI: 10.3390/jcm10112235 -
Journal of Clinical Medicine Apr 2021Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins... (Review)
Review
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins of the postsynaptic membrane resulting in damage to postsynaptic membrane, decreased number of AChRs or blocking of the receptors by autoantibodies. A number of drugs such as immune checkpoint inhibitors, penicillamine, tyrosine kinase inhibitors and interferons may induce de novo MG by altering the immune homeostasis mechanisms which prevent emergence of autoimmune diseases such as MG. Other drugs, especially certain antibiotics, antiarrhythmics, anesthetics and neuromuscular blockers, have deleterious effects on neuromuscular transmission, resulting in increased weakness in MG or MG-like symptoms in patients who do not have MG, with the latter usually being under medical circumstances such as kidney failure. This review summarizes the drugs which can cause de novo MG, MG exacerbation or MG-like symptoms in nonmyasthenic patients.
PubMed: 33917535
DOI: 10.3390/jcm10071537 -
Clinical & Experimental Optometry Mar 2022Myasthenia gravis is a rare autoimmune disease characterised by autoantibodies preventing normal function of acetylcholine receptors at the post-synaptic membrane of the... (Review)
Review
Myasthenia gravis is a rare autoimmune disease characterised by autoantibodies preventing normal function of acetylcholine receptors at the post-synaptic membrane of the neuromuscular junction. This causes weakness of skeletal muscles that can be variable and fatigable, and often manifests as ptosis and/or diplopia, with 60% of patients demonstrating ocular features at onset, and thus may present initially to eye care practitioners. Approximately 15% of patients have ocular myasthenia gravis, where symptoms remain restricted to this distribution. The majority of patients have blocking antibodies against the acetylcholine receptor, but antibodies directed against other related targets account for a smaller proportion and are associated with specific phenotypes. Associations with both thymoma and with other autoimmune phenomena (particularly thyroid disease) can occur. Clinical examination can identify characteristic findings including fatigable ptosis and Cogan's lid twitch sign. Investigations to confirm the diagnosis include simple office-based procedures such as the ice test, and testing for serum autoantibodies, as well as electrophysiological testing such as repetitive nerve stimulation and single-fibre electromyography. The management of ocular myasthenia gravis is discussed, including non-pharmacological options, pyridostigmine, corticosteroids, other immunosuppressive agents, and thymectomy. The goals of management are to alleviate symptoms, and where possible prevent chronic disability or progression to generalised myasthenia gravis.
Topics: Diplopia; Humans; Immunosuppressive Agents; Myasthenia Gravis
PubMed: 35157811
DOI: 10.1080/08164622.2022.2029683 -
Journal of Neurology Jul 2023Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair... (Review)
Review
Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair acetylcholine receptor function. Weakness of respiratory muscles represents the most severe MG manifestation, and 10-15% of all patients experience an MG crisis with the need of mechanical ventilatory support at least once in their life. MG patients with respiratory muscle weakness need active immunosuppressive drug treatment long term, and they need regular specialist follow-up. Comorbidities affecting respiratory function need attention and optimal treatment. Respiratory tract infections can lead to MG exacerbations and precipitate an MG crisis. Intravenous immunoglobulin and plasma exchange are the core treatments for severe MG exacerbations. High-dose corticosteroids, complement inhibitors, and FcRn blockers represent fast-acting treatments that are effective in most MG patients. Neonatal myasthenia is a transient condition with muscle weakness in the newborn caused by mother's muscle antibodies. In rare cases, treatment of respiratory muscle weakness in the baby is required.
Topics: Infant, Newborn; Humans; Myasthenia Gravis; Neuromuscular Junction; Neuromuscular Diseases; Muscle Weakness; Respiratory Tract Diseases
PubMed: 37101094
DOI: 10.1007/s00415-023-11733-y -
Nature Communications Feb 2022The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to...
The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; Cells, Cultured; Dendritic Spines; Hippocampus; Long-Term Synaptic Depression; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neuronal Plasticity; Neurons; Proteome; Proteomics; Pyramidal Cells; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Potentials; Mice
PubMed: 35115539
DOI: 10.1038/s41467-022-28301-z -
Nature Jul 2021Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into...
Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins. It is unclear whether neurexin-cerebellin-GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1-cerebellin-2 and neurexin-3-cerebellin-2 complexes differentially regulate NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-3 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5-13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin-cerebellin signals into postsynaptic receptor responses.
Topics: Amino Acid Motifs; Animals; Calcium-Binding Proteins; Cell Membrane; Excitatory Postsynaptic Potentials; Female; Glutamate Dehydrogenase; Male; Mice; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Protein Precursors; Receptors, AMPA; Receptors, Ionotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses
PubMed: 34135511
DOI: 10.1038/s41586-021-03661-6 -
Molecular Immunology Nov 2022Myasthenia gravis is a neuromuscular disease associated with antibodies against components of the neuromuscular junction, most often against the acetylcholine receptor... (Review)
Review
Myasthenia gravis is a neuromuscular disease associated with antibodies against components of the neuromuscular junction, most often against the acetylcholine receptor (AChR). Although several mechanisms have been postulated to explain how these autoantibodies can lead to the pathology of the disease, convincing evidence suggests that destruction of the receptor-bearing postsynaptic membrane by complement membrane attack complex is of central importance. In this review, evidence for the importance of complement, and possible relationships between autoantigen, autoantibodies, complement activation, and the destruction of the membrane are discussed. More recent insights from the results of the complement-inhibiting therapeutic antibody eculizumab are also described, and the mechanisms connecting antibody binding to complement activation are considered from a structural viewpoint.
Topics: Autoantibodies; Autoantigens; Complement Membrane Attack Complex; Complement System Proteins; Humans; Myasthenia Gravis; Receptors, Cholinergic
PubMed: 36063582
DOI: 10.1016/j.molimm.2022.08.018