In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: Results of testing patients surviving fulminant MH and unrelated low‐risk subjects

Ørding, Helle; Brancadoro, Virginia; Cozzolino, Santolo; Ellis, F. R.; Glauber, V.; Gonano, E. F.; Halsall, P.J.; Hartung, E.; Heffron, J. J. A.; Heytens, L.; Kozak‐Ribbens, G.; Kress, Hans G.; Krtvosic‐Horber, R.; Lehmann‐Horn, Frank; Mortier, W.; Nivoche, Y.; Ranklev-Twetman, Eva; Sigurdsson, Stefan; Snoeck, M.M.J.; Stieglitz, P.; Tegazzin, Vincenzo; Urwyler, Albert; Wappler, Frank

doi:10.1111/j.1399-6576.1997.tb04820.x

Cited by 286 publications

(179 citation statements)

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“…[8][9][10] This does not compare favourably with a reported sensitivity of 97% to 99% for CHCT and in vitro contracture test (IVCT), respectively. 36,37 Published data indicate that the frequency of MH-causative RyR1 mutations is population-specific, with only a few mutations accounting for the majority of MH cases in some populations. 6 By comparison, we found that p.Arg614Cys, p.Gly341Arg, and p.Gly2434Arg are the most frequent mutations in the Canadian MHS population, accounting for almost 35% of mutation-positive families.…”

Section: Discussionmentioning

confidence: 99%

“…The absence of RYR1 mutations in MHS individuals, together with the presence of discordant cases in families C-18 and C-27 and other MH families worldwide, 8,10 may be explained by the sensitivity and specificity of the CHCT, which identifies both false negatives and false positives at a low rate. 36,37,49 Another reason might be the possible involvement of as yet unrecognized genetic and environmental factors in the MHS phenotype. For example, mutations in calsequestrin (CASQ1) might be expected to cause MH, since a mouse CASQ1 knockout line displays MHS symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population. Methods In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families. Results Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations. Conclusions The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing. RésuméObjectif L'hyperthermie maligne (HM) est une maladie pharmacoge´ne´tique he´re´ditaire dominante autosomique qui se manifeste lors de l'exposition des personnes susceptibles a`des anesthe´siques haloge´ne´s ou à la succinylcholine. E´tant donne´que l'HM est principalement associe´e aux mutations au niveau du ge`ne des re´cepteurs de ryanodine de type 1 (RYR1), l'objectif de cette e´tude e´tait de de´terminer la distribution et la fre´quence des mutations RyR1 causant une HM chez la population canadienne susceptible a`l'HM (SHM). Méthode Dans cette e´tude, nous avons examine´une cohorte repre´sentative de 36 personnes canadiennes SHM This article is accompanied by an editorial. Please see Can J Anesth 2011; 58: 6.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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“…If threshold concentrations of these ligands are exceeded, MH sensitivity is diagnosed. The European in vitro contracture test (IVCT) [45] and the North American caffeine-halothane contracture test (CHCT) [46] for MH status achieve high sensitivity (close to 99%) at the cost of reduced specificity (between 78 and 93%) [47,48]. Thus both false negative and false positive diagnoses will appear, leading to discordance and apparent lack of linkage, making it difficult to determine the genetic basis of MH in many families.…”

Section: T H E M O L E C U L a R B A S I S F O R M A L I G N A N T H mentioning

confidence: 99%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

221

155

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Transient elevations of intracellular Ca2+ play a signalling role in such complex cellular functions as contraction, secretion, fertilization, proliferation, metabolism, heartbeat and memory. However, prolonged elevation of Ca2+ above about 10 µm is deleterious to a cell and can activate apoptosis. In muscle, there is a narrow window of Ca2+ dysregulation in which abnormalities in Ca2+ regulatory proteins can lead to disease, rather than apoptosis. Key proteins in the regulation of muscle Ca2+ are the voltage‐dependent, dihydropyridine‐sensitive, l‐type Ca2+ channels located in the transverse tubule and Ca2+ release channels in the junctional terminal cisternae of the sarcoplasmic reticulum. Abnormalities in these proteins play a key role in malignant hyperthermia (MH), a toxic response to anesthetics, and in central core disease (CCD), a muscle myopathy. Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCAs) return sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum. Loss of SERCA1a Ca2+ pump function is one cause of exercise‐induced impairment of the relaxation of skeletal muscle, in Brody disease. Phospholamban expressed in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA activity. Studies with knockout and transgenic mice show that gain of inhibitory function of phospholamban alters cardiac contractility and could be a causal feature in some cardiomyopathies. Calsequestrin, calreticulin, and a series of other acidic, lumenal, Ca2+ binding proteins provide a buffer for Ca2+ stored in the sarcoplasmic reticulum. Overexpression of cardiac calsequestrin leads to cardiomyopathy and ablation of calreticulin alters cardiac development.

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“…Four muscle bundles per patient were tested with the IVCT according to the European protocol and diagnosis of MHS or MHN was established. 2,3 Ryanodine contracture test The RCT was performed on fresh muscle bundles. Length and wet weight of each bundle was determined.…”

Section: In Vitro Contracture Testingmentioning

confidence: 99%

“…The ryanodine contracture test performed in addition to the IVCT may add clarity into diagnosing a patient as MH-susceptible or not. [1][2][3] Ryanodine, a plant alkaloid, causes time-and doserelated contractures of human skeletal muscle. It binds with high affinity to the ryanodine receptor protein (RYR1), a calcium channel at the sarcoplasmic reticulum.…”

mentioning

confidence: 99%

The ryanodine contracture test may help diagnose susceptiblity to malignant hyperthermia

Reuter¹,

Anetseder

Müller

et al. 2003

Can J Anesth/J Can Anesth

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P Pu ur rp po os se e: : The ryanodine contracture test (RCT) using the plant alkaloid ryanodine as the triggering agent has been proposed to reduce equivocal results of the in vitro caffeine-halothane-contracture test (IVCT), which is the accepted and standardized procedure to diagnose malignant hyperthermia (MH). However, the response of skeletal muscle of non-MH affected patients (controls) to ryanodine has not yet been characterized.M Me et th ho od ds s: : Skeletal muscle biopsies were studied in 33 controls and in six patients with a history of fulminant MH. Following the IVCT, the RCT was performed in all specimens using ryanodine 1 µM. Onset time of contracture and time to reach a contracture level of 10 mN above lowest resting tension and above predrug tension were calculated. R Re es su ul lt ts s: : With the standard IVCT, all controls were labelled MH non-susceptible; all clinically diagnosed MH patients were labelled MH susceptible. With ryanodine, control muscle differed from MH susceptible muscle regarding onset time of contracture (26 vs 3.8 min, P < 0.05) and time to reach a contracture of 10 mN ( 49 vs 12.5 min, P < 0.05; all median). Tissue viability and patient's age significantly influenced contracture times.C Co on nc cl lu us si io on ns s: : Despite the highly specific binding of ryanodine at the myocytic sarcoplasmic reticulum, the wide range of contracture times of the controls points toward heterogeneity of ryanodine receptors within physiologic limits. This may also be caused in part by tissue viability and the patients' age. The ryanodine contracture test performed in addition to the IVCT may add clarity into diagnosing a patient as MH-susceptible or not. (26 vs 3,8 min, P < 0,05) et au temps nécessaire pour obtenir une contracture de 10 mN ( 49 vs 12,5 min, P < 0,05 ; médiane Objectif : Le test de contracture à la ryanodine (TCR), qui utilise un alcaloïde de la ryania comme agent déclencheur, a été proposé pour réduire les résultats équivoques du test de contracture in vitro à la caféine-halothane (TIVC), lequel est accepté et normalisé pour le diagnostic de l'hyperthermie maligne (HM). Cependant, la réaction des muscles squelettiques des patients non affectés d'HM (témoins) à la ryanodine n'a pas encore été définie. Méthode : Des biopsies de muscles squelettiques ont été étudiées chez 33 témoins et six patients présentant des antécédents d'HM fulminante. À la suite du TIVC, le TCR a été réalisé pour tous les prélève-ments en utilisant 1 µM de ryanodine. Ont été calculés : le délai d'installation de la contracture et le temps nécessaire pour atteindre un niveau de 10 mN au-dessus de la plus faible tension de repos et au-dessus de la tension de prémédication. Résultats : Pour le TIVC standard, les témoins ont été étiquetés comme non susceptibles d'HM et les patients ayant un diagnostic d'HM, comme susceptibles d'HM. Pour le test à la ryanodine, les muscles témoins différaient des muscles susceptibles d'HM, quant au délai d'installation de la contracture

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In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: Results of testing patients surviving fulminant MH and unrelated low‐risk subjects

Abstract: The IVCT for diagnosis of MH susceptibility in Europe has a high sensitivity and a satisfactory specificity.

Cited by 286 publications

References 21 publications

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ca²⁺ signalling and muscle disease

The ryanodine contracture test may help diagnose susceptiblity to malignant hyperthermia

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In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: Results of testing patients surviving fulminant MH and unrelated low‐risk subjects

Abstract: The IVCT for diagnosis of MH susceptibility in Europe has a high sensitivity and a satisfactory specificity.

Cited by 286 publications

References 21 publications

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ca2+ signalling and muscle disease

The ryanodine contracture test may help diagnose susceptiblity to malignant hyperthermia

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Ca²⁺ signalling and muscle disease