Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyolysis

Wappler, Frank; Fiege, Marko; Steinfath, Markus; Agarwal, Kamayni; Scholz, Jens; Singh, Surjit; Matschke, Jakob; Esch, Jochen Schulte am

doi:10.1097/00000542-200101000-00019

Cited by 199 publications

(146 citation statements)

References 2 publications

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“…11 Eleven out of 12 exertional rhabdomyolysis patients had abnormal in vitro pharmacological muscle test responses and three of these patients were found to have RYR1 mutations. 10 Perhaps of even greater significance, Tobin et al 12 reported the tragic case of a 12-year-old boy who survived a malignant hyperthermia reaction during anaesthesia but who subsequently died of exertional heat stroke following a game of football. DNA analysis of the child and his father revealed a mutation in the RYR1 gene that had previously been associated with malignant hyperthermia.…”

Section: Germanymentioning

confidence: 99%

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Is there a link between malignant hyperthermia and exertional heat illness?

Hopkins

Wappler²

2007

Br J Sports Med

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Section: Germanymentioning

confidence: 99%

“…[7][8][9][10] These reports relate to the in vitro pharmacological muscle tests. Such findings have been reported from workers in Austria, 7 …”

mentioning

confidence: 99%

Is there a link between malignant hyperthermia and exertional heat illness?

Hopkins

Wappler²

2007

Br J Sports Med

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“…In some individuals MH reactions appear to be triggered by physical exercise or emotional stress. The latter observation has led to the suggestion that MH, heat stroke, and exercise-induced rhabdomyolysis might have a common denominator (2,6,7). The underlying causes of MH are abnormalities in the skeletal muscle calcium metabolism (8,9) and molecular genetic studies have mapped the primary locus of MH to chromosome 19q, the gene encoding the ryanodine receptor calcium release channel (RYR1) (2,4,10).…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

B-lymphocytes from Malignant Hyperthermia-susceptible Patients Have an Increased Sensitivity to Skeletal Muscle Ryanodine Receptor Activators

Girard

Cavagna

Padovan

et al. 2001

Journal of Biological Chemistry

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Malignant hyperthemia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. The underlying feature of MH is a hypersensitivity of the calcium release machinery of the sarcoplasmic reticulum, and in many cases this is a result of point mutations in the skeletal muscle ryanodine receptor calcium release channel (RYR1). RYR1 is mainly expressed in skeletal muscle, but a recent report demonstrated the existence of this isoform in human B-lymphocytes. As B-cells can produce a number of cytokines, including endogenous pyrogens, we investigated whether some of the symptoms seen during MH could be related to the involvement of the immune system. Our results show that (i) Epstein-Barr virus-immortalized B-cells from MH-susceptible individuals carrying the V2168M RYR1 gene mutation were more sensitive to the RYR activator 4-chloro-m-cresol and (ii) their peripheral blood leukocytes produce more interleukin (IL)-1␤ after treatment with the RYR activators caffeine and 4-chloro-m-cresol, compared with cells from healthy controls. Our result demonstrate that RYR1-mediated calcium signaling is involved in release of IL-1␤ from B-lymphocytes and suggest that some of the symptoms seen during an MH episode may be due to IL-1␤ production. Malignant hyperthermia (MH)1 is a pharmacogenetic disease triggered by volatile anesthetics and the depolarizing muscle relaxant succinylcholine in predisposed individuals (1-4). The clinical signs of an impending MH reaction are highly variable and are caused by a hypermetabolic state with muscle rigidity, metabolic acidosis, rhabdomyolysis, tachycardia, and/or an increase in body temperature (5). In some individuals MH reactions appear to be triggered by physical exercise or emotional stress. The latter observation has led to the suggestion that MH, heat stroke, and exercise-induced rhabdomyolysis might have a common denominator (2, 6, 7). The underlying causes of MH are abnormalities in the skeletal muscle calcium metabolism (8, 9) and molecular genetic studies have mapped the primary locus of MH to chromosome 19q, the gene encoding the ryanodine receptor calcium release channel (RYR1) (2, 4, 10). Approximately 50% of MH families have mutations in the RYR1 gene, and mutations have been reported in other loci (for recent reviews, see Refs. 11 and 12).The ryanodine receptors are large tetrameric oligomers that function as intracellular calcium release channels. Three different isoforms have been identified at the molecular level: type 1 (RYR1), which is preferentially expressed in skeletal muscle; type 2, which is in the heart and cerebellum; and type 3, which is in the central nervous system as well as in a variety of other tissues (13-16). RYR1 can be pharmacologically activated by a number of compounds, among which are caffeine, halothane, thymol, 4-chloro-m-cresol, E218, bastadin, polylysine, and calcium (17-21). Activation causes the channel to open and thus to a transient calcium flow from the sarcoplasmic reticulum,...

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“…Such a link is plausible, considering 1) an uncontrolled rise in intracellular skeletal muscle calcium as the most important shared pathomechanism [15]; and 2) the common occurrence of MH and ERM in a number of porcine [16], equine [17] and murine [18,19] [20]. Three of these patients had RYR1 mutations but only hot-spots sequencing had been performed at the time [20]. Based on their findings, the authors recommend performing genetic testing for MH-associated RYR1 mutations, muscle biopsies for histological examination and IVCT in patients presenting with ERM.…”

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 99%

“…Family counselling is vital to identify potentially MH-susceptible relatives [1] We performed a systematic literature review (including the patients in the studies mentioned above), based on a Pubmed search with "RYR1" and "rhabdomyolysis". This resulted in identification of several case report and small series [1,8,[21][22][23][24][25][26], and two review article [27,28] Subsequently, we also included cases from references of these articles [20,26,[29][30][31][32][33][34] and added our recent letter by Snoeck et al [35]. Finally, we added two patients from our paper on the spectrum of RYR1 related myopathies by Snoeck et al who were not included in any other publication (patients 14 and 52 [1]).…”

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 99%

RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

2016

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Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyolysis

Abstract: Regarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.

Cited by 199 publications

References 2 publications

Is there a link between malignant hyperthermia and exertional heat illness?

Is there a link between malignant hyperthermia and exertional heat illness?

B-lymphocytes from Malignant Hyperthermia-susceptible Patients Have an Increased Sensitivity to Skeletal Muscle Ryanodine Receptor Activators

RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

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