Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review

Kraeva, Natalia; Sapa, Alexander; Dowling, James J.; Riazi, Sheila

doi:10.1007/s12630-017-0865-5

Cited by 33 publications

(29 citation statements)

References 40 publications

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“…Pediatric and male predominance of heat sensitivity in humans and mice with MHS-associated mutations. Human RYR1 mutations that underlie MHS are also frequently associated with heat and/or exercise-induced rhabdomyolysis, exercise intolerance, heat-induced muscle cramps, and death 19,[38][39][40] . We conducted a retrospective cohort study and systematic review on RYR1 variants, age, gender, clinical symptoms and survival outcomes observed in heat-sensitive individuals with RYR1 variants associated with MHS.…”

Section: Resultsmentioning

confidence: 99%

“…The same information from family members, who carried the same genetic variant was collected. Clinical case reports published between 1980 and 2019 were systematically reviewed as previously described 38 to identify additional eligible patients, using the preferred reporting items for systematic reviews and meta-analysis guidelines. The statement and checklists for the systematic reviews and meta-analysis are provided as Supplementary Notes 1-3.…”

Section: Methodsmentioning

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: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…Functional studies and high-resolution modeling of RyR1 showed that the MH-associated mutations adjacent to p.Gly159Arg render the RyR1 channels more sensitive to agonists and lessen thermal stability of the RyR1, thereby conferring a temperaturesensitive phenotype to mutation carriers. 21,22 As RYR1-related awake MH episodes share genetic changes with anesthetic-induced MH, 23 dantrolene may be of value for their treatment. Dantrolene stabilizes the closed state of the RyR1 channel, thereby inhibiting excessive Ca 2?…”

Section: Discussionmentioning

confidence: 99%

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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“…It is possible that we have left out variants that are actually pathogenic using these strict criteria as many had REVEL scores >0.50 and/or were very rare but, considering all factors, were predicted as being Class 2 variants (e.g., D943N in the RYR1 gene with a REVEL score of 0.725 and MAF 0.0009) ( Table 1). The statin-tolerant controls carrying probably pathogenic variants should still be monitored for muscle symptoms during statin therapy over time since, by definition, 'awake state' phenotypes caused by pathogenic variants in MH-causing genes must be initiated by environmental triggers including but not limited to anesthesia, exertion, heat stroke and statin therapy [28,70]. The two positive controls may be at risk for MHS, but may also have other genetic variants or lifestyle habits that make them less susceptible to statin side effects or the dose of statin taken did not exceed a threshold for triggering muscle symptoms in these cases.…”

Section: Discussionmentioning

confidence: 99%

RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms

et al. 2018

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To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls. Materials & methods: Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls. Results: 12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over variants found in statintolerant controls. Subjects with probably pathogenic RYR1 or CACNA1S variants had plasma CK 5X to more than 400X the upper limit of normal in addition to having muscle symptoms. Conclusions: Genetic variants within the RYR1 and CACNA1S genes are likely to be a major contributor to the susceptibility to statin-associated muscle symptoms.

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Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review

Cited by 33 publications

References 40 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

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

RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms

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