Estimating prevalence of malignant hyperthermia susceptibility through population genomics data

Mungunsukh, Ognoon; Deuster, Patricia A.; Muldoon, Sheila M.; O’Connor, Francis G.; Sambuughin, Nyamkhishig

doi:10.1016/j.bja.2019.06.010

Cited by 9 publications

(6 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…• Isoflurane but not sevoflurane exposure increased mortality in Drosophila carrying homozygous mutations in mitochondrial complex I, and hyperoxia increased mortality associated with isoflurane administration • In heterozygous flies, carrying mutations in mitochondrial complex I, age, and hyperoxia rendered flies susceptible to mortality after exposure to isoflurane • These observations raise the possibility that heterozygous carriers of mitochondrial mutations may be more susceptible to perioperative complications after isoflurane exposure E XPOSURE to general anesthetics is very common but not without risks, and mutations in some anesthetic target proteins increase the risk of toxicity. 1 Of particular interest are mutations affecting mitochondria, because mitochondrial diseases are the most frequently inherited metabolic disorders, and mitochondrial proteins are targets of general anesthetics. 2,3 Because volatile general anesthetics inhibit the function of complex I of the mitochondrial electron transport chain, 4 they may increase the risk of perioperative complications for patients with disorders caused by mutations in complex I such as Leigh syndrome and other similar neurodegenerative disorders.…”

Section: Editor's Perspectivementioning

confidence: 99%

Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity

et al. 2020

View full text Add to dashboard Cite

Background General anesthetics influence mitochondrial homeostasis, placing individuals with mitochondrial disorders and possibly carriers of recessive mitochondrial mutations at increased risk of perioperative complications. In Drosophila, mutations in the ND23 subunit of complex I of the mitochondrial electron transport chain–analogous to mammalian NDUFS8–replicate key characteristics of Leigh syndrome, an inherited mitochondrial disorder. The authors used the ND23 mutant for testing the hypothesis that anesthetics have toxic potential in carriers of mitochondrial mutations. Methods The authors exposed wild-type flies and ND23 mutant flies to behaviorally equivalent doses of isoflurane or sevoflurane in 5%, 21%, or 75% oxygen. The authors used percent mortality (mean ± SD, n ≥ 3) at 24 h after exposure as a readout of toxicity and changes in gene expression to investigate toxicity mechanisms. Results Exposure of 10- to 13-day-old male ND23 flies to isoflurane in 5%, 21%, or 75% oxygen resulted in 16.0 ± 14.9% (n = 10), 48.2 ± 16.1% (n = 9), and 99.2 ± 2.0% (n = 10) mortality, respectively. Comparable mortality was observed in females. In contrast, under the same conditions, mortality was less than 5% for all male and female groups exposed to sevoflurane, except 10- to 13-day-old male ND23 flies with 9.6 ± 8.9% (n = 16) mortality. The mortality of 10- to 13-day-old ND23 flies exposed to isoflurane was rescued by neuron- or glia-specific expression of wild-type ND23. Isoflurane and sevoflurane differentially affected expression of antioxidant genes in 10- to 13-day-old ND23 flies. ND23 flies had elevated mortality from paraquat-induced oxidative stress compared with wild-type flies. The mortality of heterozygous ND23 flies exposed to isoflurane in 75% oxygen increased with age, resulting in 54.0 ± 19.6% (n = 4) mortality at 33 to 39 days old, and the percent mortality varied in different genetic backgrounds. Conclusions Mutations in the mitochondrial complex I subunit ND23 increase susceptibility to isoflurane-induced toxicity and to oxidative stress in Drosophila. Asymptomatic flies that carry ND23 mutations are sensitized to hyperoxic isoflurane toxicity by age and genetic background. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

show abstract

Section: Editor's Perspectivementioning

confidence: 99%

Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…39 Further, this study disclosed results to a substantially higher number of participants than previous studies of unselected cohorts, allowing for review of more procedure and ambulatory records and family history data. 30,40 Study findings, therefore, provide additional support for the emerging story that, while pathogenic or likely pathogenic variants in RYR1 may be relatively common, [26][27][28][29]33 MH episodes in individuals with such variants are not.…”

Section: Discussionmentioning

confidence: 64%

“…Incidence estimates of MH reaction with anesthetics range from 1:10,000 to 1:250,000, 4 although as many as 1:300 to 1:1,075 individuals may have pathogenic or likely pathogenic MH-associated variants. [26][27][28][29] It has been challenging to estimate penetrance of fulminant episodes in RYR1 variant carriers due to variable expressivity and exposure given that susceptible individuals may not receive a triggering agent. 17,22,30,31 Further, reactions to triggering agents can vary widely across exposures in the same individual, including multiple exposures before a reaction 6 or no reaction at all.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…Mutations in these two genes account for 50–70% of the known MH cases. A comprehensive analysis by traditional Sanger sequencing is challenging because it is costly, time-consuming, and labor-intensive, without even considering other possible genes in the genome [ 7 , 9 , 10 ]. Next-generation sequencing (NGS) analysis can help delineate the genetic diagnosis of MH and several MH-susceptible clinical presentations [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in RYR1 and CACNA1S genes account for 50 to 70% of MH cases [ 7 ]. However, according to the European Malignant Hyperthermia Group ( , accessed on 16 January 2022), currently, only 48 reported RYR1 mutations and two CACNA1S mutations have proven pathogenic according to those stringent criteria [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Gene Panel Sequencing Identifies a Novel RYR1 p.Ser2300Pro Variant as Candidate for Malignant Hyperthermia with Multi-Minicore Myopathy

Moon

Park

Kim

et al. 2022

Genes

View full text Add to dashboard Cite

Malignant hyperthermia (MH), a rare autosomal dominant pharmacogenetic disorder of skeletal muscle calcium regulation, is triggered by sevoflurane in susceptible individuals. We report a Korean having MH with multi-minicore myopathy functionally supported by RYR1-mediated intracellular Ca2+ release testing in B lymphocytes. A 14-year-old boy was admitted for the evaluation of progressive torticollis accompanied by cervicothoracic scoliosis. During the preoperative drape of the patient for the release of the sternocleidomastoid muscle under general anesthesia, his wrist and ankle were observed to have severe flexion contracture. The body temperature was 37.1 °C. To treat MH, the patient was administered a bolus of dantrolene intravenously (1.5 mg/kg) and sodium bicarbonate. After a few minutes, muscle rigidity, tachycardia, and EtCO2 all resolved. Next-generation panel sequencing for hereditary myopathy identified a novel RYR1 heterozygous missense variant (NM_000540.2: c.6898T > C; p.Ser2300Pro), which mapped to the MH2 domain of the protein, a hot spot for MH mutations. Ex vivo RYR1-mediated intracellular Ca2+ release testing in B lymphocytes showed hypersensitive Ca2+ responses to isoflurane and caffeine, resulting in an abnormal Ca2+ release only in the proband, not in his family members. Our findings expand the clinical and pathological spectra of information associated with MH with multi-minicore myopathy.

show abstract

Estimating prevalence of malignant hyperthermia susceptibility through population genomics data

Cited by 9 publications

References 13 publications

Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity

Mitochondrial Complex I Mutations Predispose Drosophila to Isoflurane Neurotoxicity

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

Gene Panel Sequencing Identifies a Novel RYR1 p.Ser2300Pro Variant as Candidate for Malignant Hyperthermia with Multi-Minicore Myopathy

Contact Info

Product

Resources

About