An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations

Moreno, Carlos A.; Hu, Sally; Kraeva, Natalia; Schuster, Frank; Johannsen, Stephan; Rueffert, Henrik; Klingler, Werner; Heytens, L.; Riazi, Sheila

doi:10.1097/aln.0000000000002813

Cited by 38 publications

(45 citation statements)

References 49 publications

(47 reference statements)

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“…We conducted a retrospective cohort study and a systematic review to provide an up-to-date, comprehensive summary of the documented cases. As anticipated from previous reports 7,41,89 , we found that young age and male gender are significant risk factors for heat-sensitivity among individuals with RYR1 variants associated with MHS. Children with MHS, especially infants, are the most vulnerable to heat-induced death.…”

Section: Discussionsupporting

confidence: 89%

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

et al. 2020

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Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.

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Section: Discussionsupporting

confidence: 89%

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

et al. 2020

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“…There is evidence that prevalence or susceptibility to MH is increased in male humans 35,36 and mice 37 . Furthermore, it has been reported that odds of developing MH are greater in males than females even with similar exposures to anesthetics 7 . Our study also shows that energy expenditure, at temperatures that do not trigger MH, is influenced by sex with differences between HET and WT mice restricted to male animals.…”

Section: Discussionsupporting

confidence: 59%

“…This energetic crisis can be triggered by volatile anesthetics, depolarizing muscle relaxants (eg, succinylcholine), intense exercise, and exposure to elevated environmental temperatures 5 . The prevalence in the human population of known MH‐causative mutations is 1:2750, 6 with variants in the ryanodine receptor 1 gene ( RYR1 ) being responsible for the majority of MH cases 7 . Polymorphism and expressed variants within the RYR1 gene have been estimated to occur in greater than 50% of people from MH‐susceptible families, although it remains unclear how many of these confer pathogenic risks 6,8,9 …”

Section: Introductionmentioning

confidence: 99%

Sex‐specific alterations in whole body energetics and voluntary activity in heterozygous R163C malignant hyperthermia‐susceptible mice

et al. 2020

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Malignant hyperthermia (MH) is characterized by induction of skeletal muscle hyperthermia in response to a dysregulated increase in myoplasmic calcium. Although altered energetics play a central role in MH, MH‐susceptible humans and mouse models are often described as having no phenotype until exposure to a triggering agent. The purpose of this study was to determine the influence of the R163C ryanodine receptor 1 mutation, a common MH mutation in humans, on energy expenditure, and voluntary wheel running in mice. Energy expenditure was measured by indirect respiration calorimetry in wild‐type (WT) and heterozygous R163C (HET) mice over a range of ambient temperatures. Energy expenditure adjusted for body weight or lean mass was increased (P < .05) in male, but not female, HET mice housed at 22°C or when housed at 28°C with a running wheel. In female mice, voluntary wheel running was decreased (P < .05) in the HET vs WT animals when analyzed across ambient temperatures. The thermoneutral zone was also widened in both male and female HET mice. The results of the study show that the R163C mutations alters energetics even at temperatures that do not typically induce MH.

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“…Incomplete penetrance affecting the expression of PSS has previously been observed in pigs (Ollivier et al, 1975;Smith & Bampton, 1978). In humans, penetrance in expression of the afflicted condition resulting from mutations in RYR1 was significantly greater in males than in females (50% versus 30%; P =0.002), despite similar levels of exposure to trigger anaesthetics (Ibarra Moreno et al, 2019).…”

Section: Tablementioning

confidence: 96%

Identification of genomic regions that contribute to wet carcass syndrome in sheep

Westhuizen¹,

MacNeil²,

Scholtz³

et al. 2019

SA J. An. Sci.

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Wet carcass syndrome (WCS), which is observed predominantly in sheep, affects carcass quality negatively. After slaughter the carcass appears to be 'wet' with a subcutaneous accumulation of watery fluid. Not all animals in a contemporary group are afflicted, and experimental attempts to induce WCS have been unsuccessful. The reported prevalence of WCS in Dorper and Dorper crosses gave rise to the hypothesis that it may have a genetic basis. Therefore, the primary objective of this investigation was to test this hypothesis using a high-density SNP assay to search loci that may predispose sheep to WCS. Muscle samples from 43 afflicted and 41 unafflicted sheep were collected from slaughterhouses in the province of Northern Cape, South Africa, and in southern Namibia. Tests against candidate genes proved uninformative, as did runs of homozygosity. Potential associations between WCS and an autosomal genetic marker were investigated further in a case-control genome-wide association study. Separate analyses for each sex were motivated because single nucleotide polymorphisms (SNPs) on the X chromosome suggested quantitative trait loci. These analyses revealed significant associations between SNP and WCS in males, but not in females. Three SNPs that reached genome-wide significance in males are in strong linkage disequilibrium with the Duchenne muscular dystrophy, 5-hydroxytryptamine receptor 2C, and Teneurin transmembrane protein 1 genes. These genes are identified as positional candidate genes, and the Duchenne muscular dystrophy, 5-hydroxytryptamine receptor 2C genes have biological effects that have been documented in other species, making them plausible functional candidate genes for WCS in sheep.

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An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations

Cited by 38 publications

References 49 publications

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation

Sex‐specific alterations in whole body energetics and voluntary activity in heterozygous R163C malignant hyperthermia‐susceptible mice

Identification of genomic regions that contribute to wet carcass syndrome in sheep

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