Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia

White, Ruth Moore; Schiemann, Anja; Burling, Sophie M.; Bjorksten, Andrew R.; Bulger, Terasa; Gillies, Robyn; Hopkins, Philip M.; Kamsteeg, Erik‐Jan; Machon, Roslyn G.; Massey, Sean; Miller, Dorota; Perry, Margaret; Snoeck, M.M.J.; Stephens, J. G.; Street, Neil; Bersselaar, Luuk R. van den; Stowell, Kathryn M.

doi:10.1016/j.bja.2022.08.029

Cited by 7 publications

(4 citation statements)

References 41 publications

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“…Due to the spread of genetic testing, many gene mutations have been found in patients with MH [28]. Not all gene mutations found in MH patients are causative of MH; functional analysis of the discovered variants is also important [29]. RYR1, CACNA1S, and Stac3 are known to be causative genes for MH, and mutations in these genes are identified in 30-70% of patients with MH by genetic testing [30,31].…”

Section: Discussionmentioning

confidence: 99%

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants

Miyoshi,

Otsuki,

Mukaida

et al. 2023

Genes

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Remimazolam is a novel general anesthetic and its safety in patients with malignant hyperthermia (MH) is unknown. We used myotubes derived from the skeletal muscle of patients with MH to examine the response to ryanodine receptor 1 (RYR1) agonist and remimazolam in MH-susceptible patients. Patients underwent muscle biopsy for the Ca2+-induced Ca2+ release (CICR) rate test, a diagnostic tool for MH in Japan. Ten patients had myotubes obtained from skeletal muscle cultures, and the genes associated with malignant hyperthermia in these patients were analyzed. The EC50 of caffeine, cresol, and remimazolam to induce intracellular calcium concentration change were compared between myotubes from CICR-negative genetic test patients and myotubes from other patients. Eight of the ten were CICR-positive, five of whom had RYR1 causative gene mutations or variants. Two patients had CICR-negative genetic tests, and as expected had the highest EC50 (the concentration of a drug that gives a half-maximal response) in response to caffeine, 4CmC and remimazolam. Three patients had a positive CICR but no known variants in RYR1 or CACNA1S (voltage-gated calcium channel subunit alpha1S). Myotubes in these patients had significantly lower EC50s for all agents than myotubes in CICR-negative patients. When myotubes from a patient who was CICR-negative and had no gene variant were used as a control, myotubes from CICR-positive patients were more hyper-responsive than controls to all stimulants used. The EC50 for remimazolam was lowest for myotubes from CICR-positive, RYR1-mutant patients, at 206 µM (corresponding to 123 µg/mL). The concentration was more than 80-times higher than the clinical concentration. RYR1 gene variants in R4645Q and W5020G were shown to be causative gene mutations for MH. Intracellular calcium in myotubes from MH patients are elevated at high concentrations of remimazolam but not at clinically used concentrations of remimazolam. Remimazolam appears to be safe to use in patients with MH.

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Section: Discussionmentioning

confidence: 99%

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants

Miyoshi,

Otsuki,

Mukaida

et al. 2023

Genes

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“…While there is a known association between certain RYR1 myopathies and MH susceptibility, including King–Denborough syndrome and central core disease, recent studies have suggested more of a continuum between RYR1 -related MH susceptibility and neuromuscular phenotypes than previously appreciated. 52 Although symptoms such as myalgias and myopathies can be common and nonspecific, recent evidence has suggested that more individuals with RYR1 -related MH susceptibility had neuromuscular symptoms compared to healthy controls. 9 In the current study, 30.3% of participants had documentation of a history of myalgia, and 6.6% had documented myopathy.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program

Yu,

Betts,

Urban

et al. 2023

Anesthesiology

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Background Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH-susceptibility gene, in unselected populations. We sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants. Methods Geisinger’s MyCode Community Health Initiative is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated. Results One hundred and fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had prior documented genetic testing for MH susceptibility; one had prior contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, hyperCKemia, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (post-operative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology. Conclusions Results demonstrate a low frequency of classic intra-anesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.

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“…The genetic laboratory is responsible for consulting the available published evidence (literature and databases) and applying prediction algorithms to eventually classify the variant as neutral or potentially MH-associated. For patient safety, individuals carrying a likely pathogenic variant RYR1 variant should be regarded to be at increased risk for MH until further diagnostic tests, i.e., an IVCT, can be performed [ 47 , 72 , 76 ].…”

Section: Clinical Diagnostic Pathwaymentioning

confidence: 99%

Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review

Frassanito

Sbaraglia

Piersanti

et al. 2023

JCM

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Malignant hyperthermia is a rare but life-threatening pharmacogenetic disorder triggered by exposure to specific anesthetic agents. Although this occurrence could affect virtually any patient during the perioperative time, the pediatric population is particularly vulnerable, and it has a five-fold higher incidence in children compared to adults. In the last few decades, synergistic efforts among leading anesthesiology, pediatrics, and neurology associations have produced new evidence concerning the diagnostic pathway, avoiding unnecessary testing and limiting false diagnoses. However, a personalized approach and an effective prevention policy focused on clearly recognizing the high-risk population, defining perioperative trigger-free hospitalization, and rapid activation of supportive therapy should be improved. Based on epidemiological data, many national scientific societies have produced consistent guidelines, but many misconceptions are common among physicians and healthcare workers. This review shall consider all these aspects and summarize the most recent updates.

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Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia

Cited by 7 publications

References 41 publications

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants

Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program

Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review

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