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What is in the Neuromuscular Junction Literature?
Lacomis, D, Puwanant, A
Journal of clinical neuromuscular disease. 2018;(2):76-84
Abstract
This update begins with myasthenia gravis and the roles of anti-agrin and cortactin antibodies. Regarding diagnosis, a report on repeated ice pack testing is highlighted as are several reports on the close correlation of electrodiagnostic testing with clinical features and the response to treatment. The incidence of head drop and associated clinical and ventilatory features are gleaned from a retrospective study. We also discuss a study that assessed the predominantly symmetric and conjugate ocular findings in MuSK-myasthenia gravis. Other topics that are covered include quality of life and preoperative risk. We then summarize the positive treatment trials of subcutaneous immunoglobulin and eculizumab. Turning to Lambert-Eaton Myasthenic Syndrome, we report on an epidemiologic study performed on the veteran affairs population, the results of the DAPPER study of 3, 4 diaminopyridine, and look to the future for other treatment options involving calcium gating modifiers.
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Pathogenic Mechanisms and Clinical Correlations in Autoimmune Myasthenic Syndromes.
Cetin, H, Vincent, A
Seminars in neurology. 2018;(3):344-354
Abstract
Autoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein-protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes.
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3.
Update in electromyography.
Pitt, M
Current opinion in pediatrics. 2013;(6):676-81
Abstract
PURPOSE OF REVIEW It is easy to forget the contribution of electromyography (EMG) to the investigation of paediatric peripheral neuromuscular disease, and this review highlights its continued importance. RECENT FINDINGS The discovery that Brown-Vialetto-van Leare disease, when associated with disorder of riboflavin metabolism, may be treatable has raised awareness of the importance of EMG for its early detection. Unexpected discovery of motor neuronopathy, which may be useful for the definition of the phenotype of several conditions, now has an added significance. The investigation of disorders of peripheral nerve cannot proceed without nerve conduction studies but particular interest has been shown in its role in the management of obstetric brachial plexus palsy, with investigation within 1 month now recommended. The key role of neurophysiology in identifying abnormalities of the neuromuscular junction, and therefore leading investigators to a diagnosis of myasthenia, is once again highlighted. EMG in muscle disease continues to have a role, particularly when identifying myotonia. SUMMARY Paediatric EMG, while a daunting technical challenge to some practitioners, remains a valuable investigative tool for the specialists in paediatric neuromuscular disorders and will continue to deliver important diagnostic information, often as quickly and accurately as other more recent innovations.
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4.
Structure of the neuromuscular junction: function and cooperative mechanisms in the synapse.
Takamori, M
Annals of the New York Academy of Sciences. 2012;:14-23
Abstract
As an overview of the structure of the neuromuscular junction, three items are described focusing on cooperative mechanisms involving the synapse and leading to muscle contraction: (1) presynaptic acetylcholine release regulated by vesicle cycling (exocytosis and endocytosis); the fast-mode of endocytosis requires a large influx of external Ca(2+) and is promoted by the activation of G protein-coupled receptors and receptor tyrosine kinases; (2) postsynaptic acetylcholine receptor clustering mediated by the muscle-specific, Dok7-stimulated tyrosine kinase (MuSK) through two signaling mechanisms: one via agrin-Lrp4-MuSK (Ig1/2 domains) and the second via Wnt-MuSK (Frizzled-like cysteine-rich domain)-adaptor Dishevelled; Wnts/MuSK and Lrp4 direct a retrograde signal to presynaptic differentiation; (3) muscle contractile machinery regulated by Ca(2+) -release and Ca(2+) -influx channels, including the depolarization-activated ryanodine receptor-1 and the receptor- and/or store-operated transient receptor potential canonical. The first mechanism is dysfunctional in Lambert-Eaton myasthenic syndrome, the second in anti-acetylcholine receptor-negative myasthenia gravis (MG), and the third in thymoma-associated MG.
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5.
Neuromuscular transmission failure in myasthenia gravis: decrement of safety factor and susceptibility of extraocular muscles.
Serra, A, Ruff, RL, Leigh, RJ
Annals of the New York Academy of Sciences. 2012;(1):129-35
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Abstract
An appropriate density of acetylcholine receptors (AChRs) and Na(+) channels (NaChs) in the normal neuromuscular junction (NMJ) determines the magnitude of safety factor (SF) that guarantees fidelity of neuromuscular transmission. In myasthenia gravis (MG), an overall simplification of the postsynaptic folding secondary to NMJ destruction results in AChRs and NaChs depletion. Loss of AChRs and NaChs accounts, respectively, for 59% and 40% reduction of the SF at the endplate, which manifests as neuromuscular transmission failure. The extraocular muscles (EOM) have physiologically less developed postsynaptic folding, hence a lower baseline SF, which predisposes them to dysfunction in MG and development of fatigue during "high performance" eye movements, such as saccades. However, saccades in MG show stereotyped, conjugate initial components, similar to normal, which might reflect preserved neuromuscular transmission fidelity at the NMJ of the fast, pale global fibers, which have better developed postsynaptic folding than other extraocular fibers.
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6.
[Genetic defects and disorders at the neuromuscular junction].
Ohno, K
Brain and nerve = Shinkei kenkyu no shinpo. 2011;(7):669-78
Abstract
Genetic defects in molecules expressed at the neuromuscular junction (NMJ) cause congenital myasthenic syndromes (CMSs), which are characterized by muscle weakness, abnormal fatigability, amyotrophy, and minor facial anomalies. Muscle weakness mostly develops under 2 years but is also sometimes seen in adults. Mutations identified to date include (i) muscle nicotinic acetylcholine receptor (AChR) subunits, (ii) rapsyn that anchors and clusters AChRs at the neuromuscular junction, (iii) agrin that is released from the nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway, (iv) muscle-specific kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to rapsyn/AChR, (v) Dok-7 that transmits the AChR-clustering signal from agrin/LRP4/MuSK to rapsyn/AChR, (vi) skeletal muscle sodium channel type 1.4 (Nav1.4) that spreads the depolarization potential from the endplate throughout muscle fibers, (vii) collagen Q that anchors acetylcholinesterase to the synaptic basal lamina, and (viii) choline acetyltransferase that resynthesizes acetylcholine from recycled choline at the nerve terminal. In addition, mutations in the heparin sulfate proteoglycan perlecan, which binds to many molecules including collagen Q and dystroglycan, causes Schwartz-Jampel syndrome. Interestingly, mutations in LRP4 cause Cenani-Lenz syndactyly syndrome but not CMS. AChR, MuSK, and LRP4 are also targets of auto-antibodies in myasthenia gravis. In addition, molecules at the NMJ are targets of many other disease states AChRs are blocked by the snake toxin alpha-bungarotoxin and the plant poison curare. The presynaptic SNARE complex is attacked by botulinum toxin. Acetylcholinesterase is inhibited by the nerve gas sarin and by organophosphate pesticides. This review focuses on the molecular bases underlying defects of AChR, rapsyn, Nav1.4, collagen Q, and choline acetyltransferase.
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Myasthenia and related disorders of the neuromuscular junction.
Spillane, J, Beeson, DJ, Kullmann, DM
Journal of neurology, neurosurgery, and psychiatry. 2010;(8):850-7
Abstract
Our understanding of transmission at the neuromuscular junction has increased greatly in recent years. We now recognise a wide variety of autoimmune and genetic diseases that affect this specialised synapse, causing muscle weakness and fatigue. These disorders greatly affect quality of life and rarely can be fatal. Myasthenia gravis is the most common disorder and is most commonly caused by autoantibodies targeting postsynaptic acetylcholine receptors. Antibodies to muscle-specific kinase (MuSK) are detected in a variable proportion of the remainder. Treatment is symptomatic and immunomodulatory. Lambert-Eaton myasthenic syndrome is caused by antibodies to presynaptic calcium channels, and approximately 50% of cases are paraneoplastic, most often related to small cell carcinoma of the lung. Botulism is an acquired disorder caused by neurotoxins produced by Clostridium botulinum, impairing acetylcholine release into the synaptic cleft. In addition, several rare congenital myasthenic syndromes have been identified, caused by inherited defects in presynaptic, synaptic basal lamina and postsynaptic proteins necessary for neuromuscular transmission. This review focuses on recent advances in the diagnosis and treatment of these disorders.
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8.
[Adverse effects of therapeutic drugs on neuromuscular junctions].
Motomura, M, Shiraishi, H, Yoshimura, T, Tsujihata, M
Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine. 2007;(8):1604-7
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The emerging diversity of neuromuscular junction disorders.
Newsom-Davis, J
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology. 2007;(1):5-10
Abstract
Research advances over the last 30 years have shown that key transmembrane proteins at the neuromuscular junction are vulnerable to antibody-mediated autoimmune attack These targets are acetylcholine receptors (AChRs) and muscle specific kinase (MuSK) in myasthenia gravis, voltage-gated calcium channels (VGCCs) in the Lambert-Eaton myasthenic syndrome (LEMS), and voltage-gated potassium channels (VGKCs) in neuromyotonia. In parallel with these immunological advances, mutations identified in genes encoding pre-synaptic, synaptic and postsynaptic proteins that are crucial to neuromuscular transmission have revealed a similar diversity of congenital myasthenic syndromes (CMS). These discoveries have had a major impact on diagnosis and management.
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10.
Does the frequency content of the surface mechanomyographic signal reflect motor unit firing rates? A brief review.
Beck, TW, Housh, TJ, Johnson, GO, Cramer, JT, Weir, JP, Coburn, JW, Malek, MH
Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology. 2007;(1):1-13
Abstract
The purpose of this review is to examine the literature that has investigated the potential relationship between mechanomyographic (MMG) frequency and motor unit firing rates. Several different experimental designs/methodologies have been used to address this issue, including: repetitive electrical stimulation, voluntary muscle actions in muscles with different fiber type compositions, fatiguing and non-fatiguing isometric or dynamic muscle actions, and voluntary muscle actions in young versus elderly subjects and healthy individuals versus subjects with a neuromuscular disease(s). Generally speaking, the results from these investigations have suggested that MMG frequency is related to the rate of motor unit activation and the contractile properties (contraction and relaxation times) of the muscle fibers. Other studies, however, have reported that MMG mean power frequency (MPF) does not always follow the expected pattern of firing rate modulation (e.g. motor unit firing rates generally increase with torque during isometric muscle actions, but MMG MPF may remain stable or even decrease). In addition, there are several factors that may affect the frequency content of the MMG signal during a voluntary muscle action (i.e. muscle stiffness, intramuscular fluid pressure, etc.), independent of changes in motor unit firing rates. Despite the potential influences of these factors, most of the evidence has suggested that the frequency domain of the MMG signal contains some information regarding motor unit firing rates. It is likely, however, that this information is qualitative, rather than quantitative in nature, and reflects the global motor unit firing rate, rather than the firing rates of a particular group of motor units.