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Malignant hyperthermia of anesthesia is a life-threatening pharmacogenetic syndrome triggered by volatile anesthetics or depolarizing muscle relaxants, characterized by uncontrolled skeletal muscle Ca²⁺ release, hypermetabolism and muscle rigidity. Variants in the skeletal muscle ryanodine receptor gene RYR1 (HGNC:10483) underlie the majority of cases and result in hyper-active Ca²⁺ release channels, predisposing carriers to crisis during anesthesia.
Inheritance is autosomal dominant with variable penetrance. Over 100 unrelated probands harbor RYR1 mutations, and segregation has been demonstrated in more than 50 multi-generation families, with 64 additional affected relatives carrying pathogenic alleles confirming cosegregation with malignant hyperthermia susceptibility (PMID:10823104; PMID:12123492; PMID:12237752). Concordant functional data from in vitro contracture tests and Ca²⁺-release assays support a definitive gene–disease relationship.
RYR1 variants are almost exclusively missense and cluster in three hot-spot domains. The classic pig “Arg614Cys” mutation (c.1840C>T (p.Arg614Cys)) has been observed in multiple pedigrees and accounts for ~5–9% of RYR1-positive cases (PMID:12237752). Over 300 unique RYR1 variants have been reported in >80 unrelated families, including de novo and founder alleles, with total probands exceeding 100 across diverse populations. No loss-of-function alleles have been linked to malignant hyperthermia susceptibility.
Functional characterization in rabbit and human cell models demonstrates that MH-associated RYR1 mutations confer hypersensitivity to physiological and pharmacological activators. Mutant channels show increased sensitivity to caffeine and 4-chloro-m-cresol, elevated resting Ca²⁺ release and reduced inactivation by Ca²⁺ and calmodulin (PMID:9030597; PMID:9334205). In vitro contracture testing of patient muscle and Ca²⁺ imaging in patient-derived myotubes consistently reproduce the hyper-excitability phenotype.
A small number of pedigrees show discordance between RYR1 genotypes and the in vitro contracture test, challenging the causative role of some variants alone (PMID:7762556). This underscores the importance of comprehensive functional validation and family studies for variant interpretation.
Extensive genetic, segregation and functional data over >30 years establish RYR1 as definitively causative for malignant hyperthermia of anesthesia. Genetic testing for known pathogenic RYR1 variants enables presymptomatic diagnosis, guides anesthetic management and permits targeted family screening. Early identification of RYR1 mutation carriers facilitates avoidance of triggering agents and rapid initiation of dantrolene therapy in acute crises.
Key Take-home: RYR1 mutation screening is a definitive, non-invasive diagnostic tool for malignant hyperthermia susceptibility that directly informs perioperative risk management.
Gene–Disease AssociationDefinitiveOver 100 unrelated probands, AD segregation in >50 families, concordant functional data Genetic EvidenceStrong
Functional EvidenceStrongExtensive in vitro contracture tests and cellular Ca2+ assays demonstrate gain-of-function effects |