Newly Published
Perioperative Medicine  |   June 2019
An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations
Author Notes
  • From the Department of Anesthesia, University of Toronto and Malignant Hyperthermia Investigation Unit, Toronto General Hospital, Toronto, Ontario, Canada (C.A.I.M., S.H., N.K., S.R.); Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany (F.S., S.J.); Department of Anaesthesiology and Intensive Care, Leipzig University Hospital, Leipzig, Germany (H.R.); Helios Klinik Schkeuditz, Schkeuditz, Germany (H.R.); Academic Hospital Sigmaringen, Sigmaringen, Germany (W.K.); Experimental Anaesthesiology, Ulm University, Ulm, Germany (W.K.); Department of Anaesthesiology, Antwerp University Hospital, Edegem, Belgium (L.H.); MH Research Unit, University of Antwerp, Wilrijk, Belgium (L.H.).
  • Part of the work presented in this article has been presented at the International Anesthesia Research Society Meeting (IARS) on April 28, 2018, in Chicago, Illinois.
    Part of the work presented in this article has been presented at the International Anesthesia Research Society Meeting (IARS) on April 28, 2018, in Chicago, Illinois.×
  • Submitted for publication October 6, 2018. Accepted for publication April 23, 2019.
    Submitted for publication October 6, 2018. Accepted for publication April 23, 2019.×
  • Correspondence: Address correspondence to Dr. Riazi: University of Toronto, 323-200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. sheila.riazi@uhn.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Neuromuscular Diseases and Drugs / Patient Safety
Perioperative Medicine   |   June 2019
An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations
Anesthesiology Newly Published on June 13, 2019. doi:10.1097/ALN.0000000000002813
Anesthesiology Newly Published on June 13, 2019. doi:10.1097/ALN.0000000000002813
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Malignant hyperthermia is a rare life-threatening disorder triggered in genetically predisposed individuals by exposure to certain anesthetics

  • The ryanodine receptor 1 (RYR1) gene, which encodes the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum, is the major malignant hyperthermia-associated locus

  • Malignant hyperthermia diagnostic mutations are more prevalent than the reported incidence of clinical malignant hyperthermia episodes because many mutation carriers are never exposed to anesthetic triggers and some may have several uneventful anesthetics before developing malignant hyperthermia reaction

What This Article Tells Us That Is New:

  • In a multicenter case-control study of 229 genotype-positive subjects with previous recorded exposure to trigger anesthetics, there were 93 malignant hyperthermia cases, for an overall penetrance for the analyzed RYR1 mutations of 40.6%

  • The probability of developing malignant hyperthermia on exposure to triggers was 0.25 among all RYR1 mutation carriers and 0.76 in survivors of malignant hyperthermia reactions (95% CI of the difference 0.41 to 0.59)

  • Young age, male sex, and the use of succinylcholine were major nongenetic risk factors influencing expression of the RYR1 mutations conferring malignant hyperthermia susceptibility

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.