Carlos A Ibarra Moreno1, Sally Hu, Natalia Kraeva, Frank Schuster, Stephan Johannsen, Henrik Rueffert, Werner Klingler, Luc Heytens, Sheila Riazi. 1. 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.).
Abstract
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.
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.
Authors: Monica Aleman; Rui Zhang; Wei Feng; Lihong Qi; Jose R Lopez; Chelsea Crowe; Yao Dong; Genady Cherednichenko; Isaac N Pessah Journal: Mol Pharmacol Date: 2020-08-06 Impact factor: 4.436
Authors: Hui J Wang; Chang Seok Lee; Rachel Sue Zhen Yee; Linda Groom; Inbar Friedman; Lyle Babcock; Dimitra K Georgiou; Jin Hong; Amy D Hanna; Joseph Recio; Jong Min Choi; Ting Chang; Nadia H Agha; Jonathan Romero; Poonam Sarkar; Nicol Voermans; M Waleed Gaber; Sung Yun Jung; Matthew L Baker; Robia G Pautler; Robert T Dirksen; Sheila Riazi; Susan L Hamilton Journal: Nat Commun Date: 2020-10-09 Impact factor: 17.694