Diagnostic Testing
The diagnostic guidelines of the European Malignant Hyperthermia Group (EMHG) provide a framework that balances the definitive but invasive and more expensive in vitro contracture test with DNA testing which lacks sensitivity.
The 2015 EMHG guidelines were published in the British Journal of Anaesthesia:
European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility
P. M. Hopkins; H. Ruffert; M. M. Snoeck; T. Girard; K. P. E. Glahn; F. R. Ellis; C. R. Muller; A. Urwyler, on behalf of The European Malignant Hyperthermia Group;
British Journal of Anaesthesia 2015;
doi: 10.1093/bja/aev225
Alternatively the guidelines can be accessed on the EMHG website:
Why is a muscle biopsy needed to confirm MH status when a familial RYR1 mutation is absent?
This is the advice in the guidelines of the European MH Group [1]. This advice arose from evidence that accumulated during the 1990s that the genetics of MH was more complex than first thought. Locus and allelic heterogeneity were pronounced but data from across Europe also showed a surprising level of phenotype-genotype discordance in families where RYR1 mutations had been identified. At first this was presumed to result from errors in phenotyping (muscle contracture testing) or genotyping. Genotyping errors were relatively easy to check by repeat sampling and testing but the muscle contracture testing was more difficult – not very easy to re-biopsy patients. Quite appropriately our genetics colleagues queried the rigour of the contracture testing but when they examined the data themselves, even those who had originally been most sceptical agreed that the phenotype-genotype discordance should not be ignored. The data providing the rationale for the guidelines were published in 2003 [2]
While the guidelines were being developed we began looking for genetic evidence that the presumed single gene model may not always apply in MH. We used transmission disequilibrium testing (TDT) for candidate loci/regions and demonstrated that several genes may influence predisposition to MH within a single family [3]. We subsequently repeated the study using pedigrees from across Europe and found similar results [4]. Around the same time, Lunardi’s group in Grenoble reported an unexpectedly high incidence of MH families with more than one RYR1 mutation and another family with a RYR1 mutation and a mutation in the CACNA1S gene that had been shown to produce functionally relevant effects [5]. It’s important to note that only a limited number of mutations were looked for in these families: major obstacles to expanding such studies are the work required to determine the functional significance of missense RYR1 variants and identification of other genes that might contribute to MH risk.
In the meantime, we have continued to explore phenotype-genotype relationships. We have demonstrated that the contracture test responses correlate with the severity of the clinical reaction in index cases and our analyses strongly implicate the degree of MH risk to be RYR1-variant specific – to such a degree that the functionally weaker variants are highly unlikely to be the sole contributors to MH susceptibility [6].
We have also been looking for evidence of involvement in other candidate genes. A European collaboration (unfortunately not yet written up by our Italian colleagues) did not find any evidence for involvement of the skeletal muscle isoform of calsequestrin, which was proposed as a likely candidate because of an apparent MH phenotype in CASQ1 null mice. Similar data from Canada are published.
Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KPE, Ellis FR, Müller CR, Urwyler A, European Malignant Hyperthermia Group. The European Malignant Hyperthermia Group guidelines for the investigation of malignant hyperthermia susceptibility. British Journal of Anaesthesia 2015; 115: 531-9
Robinson RL, Anetseder MJ, Brancadoro V, van Broekhaven C, Carsana A, Censier K, Fortunato G, Girard T, Heytens L, Hopkins PM, Jurkat-Rott K, Klingler W, Kozak-Ribbens G, Krivosic R, Monnier N, Nivoche Y, Olthoff D, Rueffert H, Sorrentino V, Tegazzin V, Mueller CR. Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing? Eur J Hum Genet 2003;11:342-8
Robinson RL, Curran JL, Ellis FR, Halsall PJ, Hall WJ, Hopkins PM, Iles DE, West SP, Shaw M-A. Multiple interacting gene products may influence susceptibility to malignant hyperthermia. Ann Hum Genet 2000; 64: 307-320
Robinson RL, Hopkins PM, Carsana A, Gilly H, Halsall PJ, Heytens L, Islander G, Jurkat-Rott K, Mueller CR, Shaw M-A. Several interacting genes influence the malignant hyperthermia phenotype. Hum Genet 2003; 112: 217-18
Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J. Presence of two different genetic traits in malignant hyperthermia families: implications for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 2002; 97: 1067-74
Carpenter D, Robinson RL, Quinnell RJ, Ringrose C, Hogg M, Casson F, Booms P, Iles DE, Halsall PJ, Steele D, Shaw M-A, Hopkins PM. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth 2009 103: 538-48