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

WHAT WE ALREADY KNOW ABOUT THIS TOPIC Malignant hyperthermia is a rare life-threatening disorder triggered in genetically predisposed individuals by exposure to certain anestheticsThe ryanodine receptor 1 (RYR1) gene, which encodes the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum, is the major malignant hyperthermia-associated locusMalignant 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 exposureto 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.