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The Journal of Biological Chemistry Aug 2023Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to...
Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca channel Ca1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, Ca1.1-R174W. Heterozygous (HET) and homozygous (HOM) Ca1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of Ca1.1 by quantitative PCR, Western blot, [H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible Ca1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the Ca1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca and Na measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. Ca1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.
Topics: Animals; Mice; Calcium; Halothane; Heat-Shock Response; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Ryanodine Receptor Calcium Release Channel; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
PubMed: 37392848
DOI: 10.1016/j.jbc.2023.104992 -
Perfusion Sep 2019Malignant hyperthermia is a well-known but potentially lethal disorder which is triggered by volatile anesthetics and depolarizing muscle relaxants. Early diagnosis and... (Review)
Review
Malignant hyperthermia is a well-known but potentially lethal disorder which is triggered by volatile anesthetics and depolarizing muscle relaxants. Early diagnosis and treatment could save lives. However, during cardiac surgery, hypothermia and cardiopulmonary bypass make the diagnosis of malignant hyperthermia extremely difficult than other surgeries. We report a case of almost-certain malignant hyperthermia, according to the clinical grading scale, in a patient undergoing on-pump coronary artery bypass grafting surgery. The patient underwent difficult weaning from cardiopulmonary bypass until intra-aortic balloon pump and temporary cardiac pacemaker had been implanted. Although dantrolene and corresponding treatments were administered recently, the patient died 12 days after surgery because of acute kidney failure and cardiac arrest. Therefore, it is important for us to previously recognize some specific signs of malignant hyperthermia during cardiopulmonary bypass to avoid severe outcomes.
Topics: Cardiopulmonary Bypass; Dantrolene; Fatal Outcome; Humans; Male; Malignant Hyperthermia; Middle Aged; Pacemaker, Artificial
PubMed: 30843472
DOI: 10.1177/0267659119833230 -
IUBMB Life Dec 2019Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body... (Review)
Review
Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body temperature to highly irreversible levels, which causes death in around three of four cases. The trigger anesthetics cause an anomalous, continued ascent in myoplasmic calcium levels. Possible mechanisms by which continuous release of sodium, calcium from skeletal muscle plasma membrane and sarcoplasmic reticulum stores respectively can produce the profound hyperthermia are discussed.
Topics: Anesthesia; Anesthetics; Calcium; Dantrolene; Humans; Malignant Hyperthermia; Muscle, Skeletal; Sodium-Calcium Exchanger; TRPC Cation Channels
PubMed: 31381266
DOI: 10.1002/iub.2138 -
Practical Neurology Oct 2020Neurologists are often asked for specific advice regarding patients with neuromuscular disease who require general anaesthesia. However, guidelines on specific... (Review)
Review
Neurologists are often asked for specific advice regarding patients with neuromuscular disease who require general anaesthesia. However, guidelines on specific neuromuscular disorders do not usually include specific guidelines or pragmatic advice regarding (regional and/or general) anaesthesia or procedural sedation. Furthermore, the medical literature on this subject is mostly limited to publications in anaesthesiology journals. We therefore summarise general recommendations and specific advice for anaesthesia in different neuromuscular disorders to provide a comprehensive and accessible overview of the knowledge on this topic essential for clinical neurologists. A preoperative multidisciplinary approach involving anaesthesiologists, cardiologists, chest physicians, surgeons and neurologists is crucial. Depolarising muscle relaxants (succinylcholine) should be avoided at all times. The dose of non-depolarising muscle relaxants must be reduced and their effect monitored. Patients with specific mutations in (ryanodine receptor 1) and less frequently in (calcium channel, voltage-dependent, L type, alpha 1S subunit) and (SH3 and cysteine rich domain 3) are at risk of developing a life-threatening malignant hyperthermia reaction.
PubMed: 33109742
DOI: 10.1136/practneurol-2020-002633 -
Cureus Sep 2020Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH) share similar clinical characteristics. These conditions can present... (Review)
Review
Neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH) share similar clinical characteristics. These conditions can present life-threatening situations due to exposure to different drugs. A similar genetic predisposition is suspected between these syndromes as well. This review aims to consolidate the knowledge about the genetics of these disorders and find possible correlations among them to frame the best possible approaches using different drugs without producing life-threatening complications that can be preventable. As a method, we collected data using PubMed with a Medical Subject Headings (MeSH) strategy. The inclusion criteria were as follows: full papers, studies conducted on humans, papers published in the English language, and study types that included case reports, journal articles, multicenter studies, clinical studies, observational studies, or clinical trials. Studies involving animals, articles that were without a visible abstract, study types that included clinical reviews, systematic reviews, or meta-analyses were excluded. 146 papers were reviewed, and 130 papers were removed for no possible extraction of data, duplication of the data, or the study outcome was not compatible with the objective of this review. Ultimately, a total of 17 papers were used for the discussion of this article. As a result of this review, we found no genetic association between NMS, SS, and MH development. Finally, we conclude that NMS, SS, and MH presentation are caused by different mutations which are not associated. However, because of the life-threatening clinical presentation of these conditions, genetic tests should be suggested in patients with a family history of these disorders before administering any pertinent drug that increases the risk of developing all these syndromes.
PubMed: 33123448
DOI: 10.7759/cureus.10635 -
Canadian Journal of Anaesthesia =... Jun 2021
Topics: Humans; Hyperthermia; Malignant Hyperthermia; Metabolomics; Muscle, Skeletal; Ryanodine Receptor Calcium Release Channel
PubMed: 33532996
DOI: 10.1007/s12630-020-01896-x -
Pharmacogenomics Jan 2020Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.'... (Review)
Review
Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.
Topics: Anesthesia; Anesthesiology; Apnea; Child; Child, Preschool; Humans; Malignant Hyperthermia; Pain; Pain Management; Pediatrics; Precision Medicine; Succinylcholine
PubMed: 31849281
DOI: 10.2217/pgs-2019-0108 -
Medicine Aug 2021Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise...
INTRODUCTION
Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM.
METHODS
The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM.
DISCUSSION
This study will increase knowledge of the full spectrum of neuromuscular and multisystem features of RYR1-related MH and ERM and will establish a well-characterized baseline cohort for future studies on RYR1-related disorders. The results of this study are expected to improve recognition of RYR1-related symptoms, counselling and a more personalized approach to patients affected by these conditions. Furthermore, results will create new insights in the role of the immune system in the pathophysiology of MH and ERM.
TRIAL REGISTRATION
This study was pre-registered at ClinicalTrials.gov (ID: NCT04610619).
Topics: Clinical Protocols; Cohort Studies; Cross-Sectional Studies; Humans; Malignant Hyperthermia; Prospective Studies; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel; Surveys and Questionnaires
PubMed: 34414986
DOI: 10.1097/MD.0000000000026999 -
Cureus Apr 2024As a result of the widespread prevalence of anesthetic usage, anesthesia-related complications are well studied, ranging from benign postoperative nausea and vomiting to... (Review)
Review
As a result of the widespread prevalence of anesthetic usage, anesthesia-related complications are well studied, ranging from benign postoperative nausea and vomiting to potentially fatal complications, such as paralysis, malignant hyperthermia, and death. However, one intersection that still needs further analysis is the relationship between vector-borne illnesses (VBIs) and anesthetic complications. With the advent of climate change and global warming, what were previously endemic vectors have spread far beyond their typical regions, resulting in the spread of VBI. As the incidence of VBIs rapidly increases in the United States, operations for diagnostic testing, and thus the identification and treatments of these VBIs, have significantly diminished. A literature review was conducted to analyze case reports of patients with VBIs and anesthetic concerns with sources from PubMed and Google Scholar databases, and a wide range of complications were found.
PubMed: 38586230
DOI: 10.7759/cureus.57517 -
ENeuro Aug 2023Volatile anesthetics reduce excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms which include inhibition of depolarization-evoked increases...
Volatile anesthetics reduce excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms which include inhibition of depolarization-evoked increases in presynaptic Ca concentration and blockade of postsynaptic excitatory glutamate receptors. The presynaptic sites of action leading to reduced electrically evoked increases in presynaptic Ca concentration and Ca-dependent exocytosis are unknown. Endoplasmic reticulum (ER) of Ca release via ryanodine receptor 1 (RyR1) and uptake by SERCA are essential for regulation intracellular Ca and are potential targets for anesthetic action. Mutations in sarcoplasmic reticulum (SR) release channels mediate volatile anesthetic-induced malignant hyperthermia (MH), a potentially fatal pharmacogenetic condition characterized by unregulated Ca release and muscle hypermetabolism. However, the impact of MH mutations on neuronal function are unknown. We used primary cultures of postnatal hippocampal neurons to analyze volatile anesthetic-induced changes in ER Ca dynamics using a genetically encoded ER-targeted fluorescent Ca sensor in both rat and mouse wild-type (WT) neurons and in mouse mutant neurons harboring the T4826I MH-susceptibility mutation. The volatile anesthetic isoflurane reduced both baseline and electrical stimulation-evoked increases in ER Ca concentration in neurons independent of its depression of presynaptic cytoplasmic Ca concentrations. Isoflurane and sevoflurane, but not propofol, depressed depolarization-evoked increases in ER Ca concentration significantly more in mouse T4826I mutant neurons than in wild-type neurons. The T4826I mutant neurons also showed markedly greater isoflurane-induced reductions in presynaptic cytosolic Ca concentration and synaptic vesicle (SV) exocytosis. These findings implicate RyR1 as a molecular target for the effects of isoflurane on presynaptic Ca handling.
Topics: Rats; Mice; Animals; Calcium; Isoflurane; Malignant Hyperthermia; Ryanodine Receptor Calcium Release Channel; Rodentia; Endoplasmic Reticulum; Neurons; Hippocampus
PubMed: 37591734
DOI: 10.1523/ENEURO.0114-23.2023