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

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New 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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Results of Contracture Tests with Halothane, Caffeine, and Ryanodine Depend on Different Malignant Hyperthermia-associated Ryanodine Receptor Gene Mutations

Anesthesiology ◽

10.1097/00000542-200208000-00010 ◽

2002 ◽

Vol 97 (2) ◽

pp. 345-350 ◽

Cited By ~ 16

Author(s):

Marko Fiege ◽

Frank Wappler ◽

Ralf Weisshorn ◽

Mark Ulrich Gerbershagen ◽

Markus Steinfath ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Time Course ◽

Clinical Symptoms ◽

Receptor Gene ◽

Gene Mutations ◽

Onset Time ◽

Release Channel ◽

Ryr1 Gene

Background More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine. Methods Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 microm ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene. Results In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene. Conclusions The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans.

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Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia

Muscle & Nerve ◽

10.1002/mus.20084 ◽

2004 ◽

Vol 30 (3) ◽

pp. 356-365 ◽

Cited By ~ 51

Author(s):

Monica Aleman ◽

Joyce Riehl ◽

Brian M. Aldridge ◽

Richard A. Lecouteur ◽

Jeffrey L. Stott ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Ryanodine Receptor 1

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Malignant hyperthermia mutation sites in the Leu2442–Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area

Biochemical Journal ◽

10.1042/bj20060902 ◽

2006 ◽

Vol 401 (1) ◽

pp. 333-339 ◽

Cited By ~ 18

Author(s):

Mark L. Bannister ◽

Tomoyo Hamada ◽

Takashi Murayama ◽

Peta J. Harvey ◽

Marco G. Casarotto ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Structural Studies ◽

Amino Acid Residues ◽

Domain Interaction ◽

Closed State ◽

Interdomain Interaction ◽

Ryanodine Receptor 1 ◽

Domain Peptide ◽

Interdomain Interactions

To explain the mechanism of pathogenesis of channel disorder in MH (malignant hyperthermia), we have proposed a model in which tight interactions between the N-terminal and central domains of RyR1 (ryanodine receptor 1) stabilize the closed state of the channel, but mutation in these domains weakens the interdomain interaction and destabilizes the channel. DP4 (domain peptide 4), a peptide corresponding to residues Leu2442–Pro2477 of the central domain, also weakens the domain interaction and produces MH-like channel destabilization, whereas an MH mutation (R2458C) in DP4 abolishes these effects. Thus DP4 and its mutants serve as excellent tools for structure–function studies. Other MH mutations have been reported in the literature involving three other amino acid residues in the DP4 region (Arg2452, Ile2453 and Arg2454). In the present paper we investigated the activity of several mutants of DP4 at these three residues. The ability to activate ryanodine binding or to effect Ca2+ release was severely diminished for each of the MH mutants. Other substitutions were less effective. Structural studies, using NMR analysis, revealed that the peptide has two α-helical regions. It is apparent that the MH mutations are clustered at the C-terminal end of the first helix. The data in the present paper indicates that mutation of residues in this region disrupts the interdomain interactions that stabilize the closed state of the channel.

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