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Acta Anaesthesiologica Scandinavica Sep 2015Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can... (Review)
Review
BACKGROUND
Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene.
METHODS
For this review a large litterature search was carried out and the Swedish MH database consisting of 436 probands who have undergone in vitro muscle contraction test (IVCT) during 1984-2014 was analyzed.
RESULTS
Twelve different MH causative mutations have been found in Swedish patients so far. These mutations lead to a disturbed calcium balance in striated muscle tissue. A muscle biopsy for the IVCT or finding of an approved causative mutation are required for the diagnosis.
CONCLUSION
A Malignant Hyperthermia susceptible (MHS) patient should be anesthetized with trigger-free anesthesia. There are a few reports of MH-like reactions in patients unrelated to anesthesia. The outcome is dependent on early recognizing of the reaction and fast disconnection of the trigger agents and administration of dantrolene.
Topics: Anesthesia; Humans; Malignant Hyperthermia; Registries; Sweden
PubMed: 25989378
DOI: 10.1111/aas.12541 -
Neuromuscular Disorders : NMD Oct 2023Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in...
Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.
Topics: Animals; Humans; Acute Disease; Calcium; Malignant Hyperthermia; Mutation; Pancreatitis; Ryanodine Receptor Calcium Release Channel
PubMed: 37783627
DOI: 10.1016/j.nmd.2023.09.003 -
Physiological Genomics Feb 2017A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility... (Review)
Review
A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.
Topics: Calcium Channels; Calcium Channels, L-Type; Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Mutation; Pharmacogenetics; Ryanodine Receptor Calcium Release Channel
PubMed: 28011884
DOI: 10.1152/physiolgenomics.00126.2016 -
Advances in Anesthesia Dec 2019
Review
Topics: Calcium Channels, L-Type; Calcium-Binding Proteins; Calsequestrin; Comorbidity; Dantrolene; Genetic Predisposition to Disease; Humans; Incidence; Malignant Hyperthermia; Mitochondrial Proteins; Muscle Relaxants, Central; Perioperative Care; Prevalence; Ryanodine Receptor Calcium Release Channel
PubMed: 31677658
DOI: 10.1016/j.aan.2019.08.003 -
Ugeskrift For Laeger Jul 2017Hyperthermia is an uncontrolled elevation of body temperature exceeding the body's ability to dissipate heat. Hyperthermia can result in dangerously high core... (Review)
Review
Hyperthermia is an uncontrolled elevation of body temperature exceeding the body's ability to dissipate heat. Hyperthermia can result in dangerously high core temperatures and can rapidly become fatal. Common causes include heat stroke, malignant hyperthermia, serotonin syndrome, neuroleptic syndrome, a few endocrine emergencies as well as numerous intoxications. Rapid diagnosis and prompt cooling are pivotal, since the condition triggers a cascade of metabolic events which may progress to irreversible injury or death. Ice-water immersion and evaporative cooling are the methods of choice.
Topics: Adrenal Insufficiency; Critical Pathways; Fever; Heat Stroke; Humans; Hypothermia, Induced; Malignant Hyperthermia; Neuroleptic Malignant Syndrome; Pheochromocytoma; Serotonin Syndrome; Thyroid Crisis
PubMed: 28789764
DOI: No ID Found -
Anesthesiology Feb 2016
Topics: Calcium Channels; Heat Stress Disorders; Humans; Malignant Hyperthermia; Ryanodine Receptor Calcium Release Channel
PubMed: 26785434
DOI: 10.1097/ALN.0000000000000980 -
Journal of Pediatric Ophthalmology and... May 2018
Review
Topics: DNA; Humans; Malignant Hyperthermia; Motor Neurons; Muscle Contraction; Muscle, Skeletal; Mutation; Ryanodine Receptor Calcium Release Channel
PubMed: 29796677
DOI: 10.3928/01913913-20180409-04 -
Sports Medicine (Auckland, N.Z.) Sep 2020Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical... (Review)
Review
Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane anesthetics or succinylcholine, which leads to a rapid, unregulated release of calcium (Ca) within the skeletal muscles inducing a positive-feedback loop within the excitation-contraction coupling mechanism that culminates in heat stroke-like symptoms, if not rapidly recognized and treated. Rare cases of awake MH, independent of anesthesia exposure, occur during exercise and heat stress. It has been suggested that EHS and MH are mediated by similar mechanisms, including mutations in Ca regulatory channels within the skeletal muscle. Rapid cooling, which is the most effective treatment for EHS, is ineffective as an MH treatment; rather, a ryanodine receptor antagonist drug, dantrolene sodium (DS), is administered to the victim to prevent further muscle contractions and hyperthermia. Whether DS can be an effective treatment for EHS victims remains uncertain. In the last decade, multiple reports have suggested a number of mechanistic links between EHS and MH. Here, we discuss aspects related to the pathophysiology, incidence, diagnosis and treatment. Furthermore, we present evidence regarding potential overlapping mechanisms between EHS and MH and explore current knowledge to establish what is supported by evidence or a lack thereof (i.e. conjecture).
Topics: Anesthetics; Calcium; Calcium Channel Blockers; Dantrolene; Heat Stroke; Humans; Malignant Hyperthermia; Muscle Contraction; Ryanodine Receptor Calcium Release Channel
PubMed: 32632746
DOI: 10.1007/s40279-020-01318-4 -
Current Opinion in Neurology Oct 2018We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate... (Review)
Review
PURPOSE OF REVIEW
We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate approach to interpret the risks.
RECENT FINDINGS
An increasing number of neuromuscular phenotypes have been linked to malignant hyperthermia susceptibility (MHS). This is for an important part due to the highly variable phenotype associated with mutations in the ryanodine receptor 1 gene (RYR1), the gene most frequently associated with MHS. A RYR1-mutation or a clinical RYR1-phenotype does not automatically translate in MHS, but precautions should be taken nonetheless. In addition, several other genes and phenotypes are now considered to be associated with MHS. In contrast, several neuromuscular diseases that were long thought to be linked to MHS are now known to cause malignant hyperthermia-like reactions instead of malignant hyperthermia. This is highly relevant as not only the given preoperative advice differs, but also acute treatment.
SUMMARY
This review provides a summary of current evidence linking certain neuromuscular diseases to malignant hyperthermia or malignant hyperthermia-like reactions. We provide a guide for the clinician, to determine which patients are at risk of malignant hyperthermia or malignant hyperthermia-like reactions perioperatively, and to ensure adequate treatment in case such a severe acute complication occurs.
Topics: Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Neuromuscular Diseases; Ryanodine Receptor Calcium Release Channel
PubMed: 30015672
DOI: 10.1097/WCO.0000000000000592 -
A&A Practice Jun 2021
Topics: Hemodynamics; Humans; Hyperthermia; Malignant Hyperthermia
PubMed: 34161308
DOI: 10.1213/XAA.0000000000001472