Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility

Butala, Brian; Brandom, Barbara W.

doi:10.1007/s12630-017-0815-2

Cited by 15 publications

(13 citation statements)

References 22 publications

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“…While many children experienced life-threatening responses to heat, adults with similar RYR1 mutations generally experienced only muscle cramps or exercise intolerance (Supplementary Datas 1 and 2 ). Similar to previously reported findings for anesthetic-induced MH cases 41 , 42 , the proportion of heat-sensitive patients observed in male carriers of RYR1 variants was significantly higher compared to that of the female carriers (Fig. 1b, c ).…”

Section: Resultssupporting

confidence: 91%

“…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%

“…MHS has also been associated with a muscular phenotype in human males 41 . While we did not detect significance differences in body weight, lean mass, metabolic rate, energy preference, and activity between YS and WT mice at basal condition, we found a small but significant decrease in overall fat mass in the YS mice, despite increased food consumption ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…37 Recently, male sex and body build subjectively assessed as muscular have been reported as independent predictors of MH susceptibility. 39 However, whether a larger muscle mass is associated with MH sex discrepancy warrants objective assessment. On the whole, the pathomechanism leading to sex differences in the penetrance of MH is still unknown, but epigenetic RYR1 allele silencing has been ruled out as a cause of reduced penetrance of MH susceptibility in females.…”

Section: Penetrance Of Malignant Hyperthermiamentioning

confidence: 99%

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

Moreno

Kraeva

et al. 2019

Anesthesiology

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M alignant hyperthermia (MH) is a rare life-threatening disorder caused by dysregulation of intracellular calcium homeostasis in skeletal muscle and triggered by exposure to certain anesthetics in genetically predisposed individuals. 1 A progressively better understanding of the pathomechanism of MH, advances in anesthesia monitoring, and the introduction of dantrolene have been crucial in reducing MH mortality, which remains around 10%. 2 Variants in ryanodine receptor 1 (RYR1), 3 calcium voltage-gated channel subunit alpha1 S (CACNA1S), 4-6 and in SH3 and cysteine rich domain 3 (STAC3) genes 7 are associated with MH. The RYR1 gene-encoding the Ca 2+ release channel of skeletal muscle sarcoplasmic reticulum (RyR1)-is the major MH-associated locus, involved in more than half of MH cases, whereas variants in CACNA1S and STAC3 account for less than 1%. At present, 48 RYR1 and 2 CACNA1S variants are aBStract Background: Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. Methods: In this multicenter case-control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. results: The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband's median age was 12 yr (interquartile range 6 to 32.5). conclusions: Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient's age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.

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“…[5][6][7] The awake episodes are rare, and present with non-specific symptoms ranging from hyperthermia, muscle cramps, exertional pain, and rhabdomyolysis to a lifethreatening hypermetabolic reaction in physically fit and seemingly healthy individuals often without a personal or family history of MH, which makes the diagnosis challenging. [7][8][9][10] We report two fatal cases of awake MH episodes in one extended family with a strong history of anesthetic-induced MH episodes and deaths demonstrating the close connection between anesthesia-induced MH and awake MH episodes. This report is intended to raise awareness among patients and medical personnel (anesthesiologists, emergency department [ED], intensive care physicians, and nurses) to the possibility of life-threatening MH episodes that may develop in MHS individuals in the absence of general anesthesia.…”

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confidence: 98%

Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series

Zvaritch

Gillies

Kraeva

et al. 2019

Can J Anesth/J Can Anesth

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Purpose The present report of two fatal awake malignant hyperthermia (MH) episodes in an MH susceptible (MHS) family is intended to raise awareness among medical personnel and MHS individuals to the possibility of lifethreatening non-anesthesia-triggered MH episodes and to provide a strong incentive for development of effective preventive measures.Clinical features Two young athletic males (28 and 16 yr old), members of the same extended family with a history of anesthesia-related MH episodes and deaths, succumbed ten years apart on two different continents, with symptoms unrelated to anesthesia but strikingly similar to typical anesthetic-induced MH. Both suffered an abrupt surge in body temperature, tachycardia, tachypnea, muscle rigidity, hyperkalemia, and respiratory and metabolic acidosis. Despite aggressive resuscitation attempts, both developed cardiac arrest and died shortly upon arrival to hospital emergency departments. Autopsy analyses were negative for drugs, alcohol, or bacterial infection. Individual and familial genetic analyses revealed a novel, potentially pathogenic RYR1 variant (p.Gly159Arg) that co-segregates with the MHS phenotype in the family. Both fatal awake MH episodes are hypothesized to have been triggered by physical exertion compounded with a febrile illness that in one case was due to influenza type A. Conclusions Life-threatening awake MH episodes may develop in some MHS individuals in the absence of anesthetic triggers. Potential triggers can be physical exertion in combination with a febrile illness. Malignant hyperthermia susceptible patients are recommended to be vaccinated against flu and restrict physical activities when febrile, wear an MH alert bracelet, and inform medical personnel of their MH history. Oral dantrolene is suggested to be available to MHS patients for administration with the early signs of awake MH. RésuméObjectif Ce compte-rendu de deux épisodes fatals d'hyperthermie maligne (HM) survenus en communauté, sans anesthésie, dans une famille susceptible à l'HM

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Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility

Abstract: Muscular body build and male sex are strongly associated with MHS.

Cited by 15 publications

References 22 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

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

Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series

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