Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Abstract

Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to B30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive

Frequency and localization of mutations in the 106 exons of theRYR1 gene in 50 individuals with malignant hyperthermia

“…However, since the large size of the RYR1 gene (106 exons) makes genetic analysis very laborious and expensive, mutation screening is preferentially performed only in those exons where known mutations are clustered [Barone et al, 1999;Brandt et al, 1999;Lynch et al, 1999;Galli et al, 2002;Robinson et al, 2003;Tilgen et al, 2003;Tammaro et al, 2003;Sambuughin et al, 2001]. This approach has resulted in the identification of mutations in the RYR1 gene in approximately 30-50% of the probands identified as MHS at the in vitro contraction test (IVCT) [European Malignant hyperpyrexia Group, 1984;Robinson et al, 2003], while analysis of the entire RYR1 coding sequence is only rarely performed [Sambuughin et al, 2005;Monnier et al, 2005]. Overall, this may generate a bias that favors extensive identification of mutations in specific areas of the RYR1 gene while limiting the identification of additional regions where mutations may also occur.…”

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

“…Discordance between CHCT and genetic studies has already been reported (26)(27)(28)(29)(30), indicating that some familial mutations are not found in some MHS members of the family. It is also possible that this discordant individual has another mutation in another part of RYR1 not analyzed or in another gene related to MH (4)(5)(6)(7).…”

Malignant hyperthermia in India

“…Genetic research into the condition implicated the ryanodine receptor gene (RYR1) located on chromosome 19 [4,5], and DNA testing is now used routinely for diagnosis before muscle biopsy when a familial RYR1 mutation is known [6]. However, the number and nature of RYR1 variants [7] and the increasingly perceived complexity of the genetics of MH [8][9][10] , potassium concentration 6 mmol.l )1 and creatine kinase concentration 29 900 IU.l . Later, he developed disseminated intravascular coagulation with haematuria and died 12 h after the initial episode.…”