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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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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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Creatine supplementation does not alter neuromuscular recovery after eccentric exercise.
Boychuk, KE, Lanovaz, JL, Krentz, JR, Lishchynsky, JT, Candow, DG, Farthing, JP
Muscle & nerve. 2016;(3):487-95
Abstract
INTRODUCTION The purpose of this study was to investigate the effects of creatine (CR) supplementation on recovery after eccentric exercise (ECC). METHODS Fourteen men were assigned randomly to ingest 0.3 g/kg of CR or placebo (PL) before and during recovery (48 hours) from 6 sets of 8 repetitions of ECC. Maximal voluntary contraction (MVC), voluntary activation (VA), muscle thickness (MT), electromyography (EMG), contractile properties, and soreness were assessed. RESULTS MVC, evoked twitch torque, and rate of torque development decreased for both groups immediately after ECC and recovered at 48 hours. MT increased and remained elevated at 48 hours for both groups. Soreness increased similarly for both groups. EMG activation was higher for CR versus PL only at 48 hours. There were no group differences for torque, total work, or fatigue index during ECC. CONCLUSIONS CR supplementation before and during recovery from ECC had no effect on strength, voluntary activation, or indicators of muscle damage. Muscle Nerve 54: 487-495, 2016.
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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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A single-fibre electromyography study of neuromuscular transmission in patients with cluster headache.
Domitrz, I, Gaweł, M, Domitrz, W, Kostera-Pruszczyk, A, Kwieciński, H
Neurologia i neurochirurgia polska. 2012;(2):140-4
Abstract
BACKGROUND AND PURPOSE Mutations of CACNA1A, which encodes a neuronal P/Q Ca2+ channel, are present in patients with familial hemiplegic migraine, and possibly in other types of migraine as well. This calcium channel is also involved in neuromuscular transmission. In our previous study we confirmed that the single-fibre electromyography (SFEMG) method can demonstrate a neuromuscular transmission deficit in migraine with aura. The aim of our present study was to estimate the neurotransmitter dysfunction in cluster headache and to compare the results between patients with cluster headache and those with migraine with aura. MATERIAL AND METHODS We selected 6 patients with cluster headache and 6 patients with migraine with typical aura. SFEMG of the voluntarily activated extensor digitorum communis muscle was performed. RESULTS The SFEMG results were in the normal range in the cluster headache group and in the healthy controls. Slight neuromuscular transmission disturbances were present in patients with migraine with aura. CONCLUSIONS The abnormal neuromuscular transmission detectable by SFEMG may reflect a genetically determined dysfunction of the P/Q Ca2+ channels in a group of migraineurs with aura. Conversely, absence of neuromuscular abnormalities in cluster headache patients could be explained by different aetiology not resulting in channelopathy. Single-fibre electromyography could be a helpful tool in clinically questionable cases in differentiating between cluster headache and migraine with aura.
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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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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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Neuromuscular electrical stimulation increases muscle protein synthesis in elderly type 2 diabetic men.
Wall, BT, Dirks, ML, Verdijk, LB, Snijders, T, Hansen, D, Vranckx, P, Burd, NA, Dendale, P, van Loon, LJ
American journal of physiology. Endocrinology and metabolism. 2012;(5):E614-23
Abstract
Physical activity is required to attenuate the loss of skeletal muscle mass with aging. Short periods of muscle disuse, due to sickness or hospitalization, reduce muscle protein synthesis rates, resulting in rapid muscle loss. The present study investigates the capacity of neuromuscular electrical stimulation (NMES) to increase in vivo skeletal muscle protein synthesis rates in older type 2 diabetes patients. Six elderly type 2 diabetic men (70 ± 2 yr) were subjected to 60 min of one-legged NMES. Continuous infusions with L-[ring-¹³C₆]phenylalanine were applied, with blood and muscle samples being collected regularly to assess muscle protein synthesis rates in both the stimulated (STIM) and nonstimulated control (CON) leg during 4 h of recovery after NMES. Furthermore, mRNA expression of key genes implicated in the regulation of muscle mass were measured over time in the STIM and CON leg. Muscle protein synthesis rates were greater in the STIM compared with the CON leg during recovery from NMES (0.057 ± 0.008 vs. 0.045 ± 0.008%/h, respectively, P < 0.01). Skeletal muscle myostatin mRNA expression in the STIM leg tended to increase immediately following NMES compared with the CON leg (1.63- vs. 1.00-fold, respectively, P = 0.07) but strongly declined after 2 and 4 h of recovery in the STIM leg only. In conclusion, this is the first study to show that NMES directly stimulates skeletal muscle protein synthesis rates in vivo in humans. NMES likely represents an effective interventional strategy to attenuate muscle loss in elderly individuals during bed rest and/or in other disuse states.
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Muscle performance and physical function are associated with voluntary rate of neuromuscular activation in older adults.
Clark, DJ, Patten, C, Reid, KF, Carabello, RJ, Phillips, EM, Fielding, RA
The journals of gerontology. Series A, Biological sciences and medical sciences. 2011;(1):115-21
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Abstract
BACKGROUND Muscle power is related to mobility function in older adults, and effective power production requires rapid neuromuscular activation. Accordingly, this study examines the association of neuromuscular activation rate with muscle performance in persons of different age and mobility function. METHODS Participants were recruited to three experimental groups: middle-aged healthy adults (MH), older healthy adults (OH), and older adults with mobility limitations (OML). OH and OML were primarily differentiated by performance on the Short Physical Performance Battery (SPPB). Muscle performance (acceleration and power) and electromyography (EMG) were recorded during a maximal-effort leg press task at an absolute resistance (260 N) and at a relative resistance (70% of the one-repetition maximum [1 RM]). Neuromuscular activation rate was quantified as pre-movement time (duration between EMG onset and movement onset) and the rate of EMG rise. RESULTS Pre-movement time, rate of EMG rise, leg press acceleration, and leg press power were lower in OML relative to MH and OH but did not differ between OH and MH, with the exception of power at 70% 1RM. Across all older participants, rate of EMG rise was positively associated with acceleration, power, and the SPPB score. CONCLUSIONS Slowing of neuromuscular activation rate is associated with compromised dynamic muscle performance, which may contribute to mobility limitations in some older adults. Future research should identify the precise neurophysiological impairments that contribute to declines in neuromuscular activation rate and mobility function with aging.
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[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.