Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept

Sheila Riazi, M.Sc., M.D.; Natalia Kraeva, Ph.D.; Philip M. Hopkins, M.D., F.R.C.A.

Disclosures

Anesthesiology. 2018;128(1):168-180. 

In This Article

Summary and Implication for Anesthesiologists

With the discovery of genes associated with MH (RYR1, CACNA1S, and STAC3) and developments in genetic screening tools, such as next-generation sequencing, our understanding of the genetics of MH has improved dramatically. The cost effectiveness of next-generation sequencing has enabled genetic testing for MH susceptibility to be a viable first-line diagnostic test for patients suspected of having an MH reaction under anesthesia and for relatives of known MH cases in many countries.

However, initial experience with next-generation sequencing–based whole exome sequencing studies has not brought about an anticipated increase in the sensitivity and specificity of MH genetic testing. Whole exome sequencing applied to MH cohorts has revealed that up to 50% of MH–susceptible individuals do not carry potentially pathogenic variants in known MH–associated genes, corroborating previous evidence for the genetic heterogeneity of MH susceptibility. Additionally, due to the possible presence of more than one pathogenic variant in the same family, MH susceptibility cannot be ruled out for individuals who do not carry a familial variant, leaving muscle contracture testing as the only reliable diagnostic test for MH susceptibility for such patients. The specificity (true negative rate) of genetic testing is limited by the fact that of more than 200 RYR1 variants identified in MH families, only 35 RYR1 and 2 CACNA1S variants are sufficiently characterized to be regarded as pathogenic for MH. The majority of newly identified RYR1 and CACNA1S variants remain to be functionally evaluated as to their role in MH. Individuals carrying variants of unknown significance in these genes should therefore be considered as being at risk of developing MH under anesthesia and should be offered contracture testing to ascertain their MH status.

The relatively low cost of whole exome sequencing, the prevalence of rare variants of unknown significance in RYR1 and CACNA1S, and the designation of these variants of unknown significance as reportable incidental findings has already led to many people under investigation for other diseases or even those just curious about their genetic heritage being labeled as potentially at risk of developing MH. Such labeling is not risk-neutral for anesthesia and can also have implications for the individuals and their family with respect to eligibility for certain occupations, ease of access to insurance policies, and concerns regarding some overseas travel. We would therefore question the ethics of offering sequencing of RYR1 and CACNA1S to individuals at low a priori risk without appropriate counseling and funded access to definitive in vitro contracture testing for MH susceptibility diagnosis should variants of unknown significance be found.

The phenotypic variability exposed in recent studies of RYR1-related disorders has taught us that abnormalities in this gene may confer not only a potentially life-threatening reaction to anesthesia but may predispose individuals to myopathies, metabolic derangements, EHI/ER and even possibly bleeding disorders. Specifically, anesthesiologists should insist on a genetic workup for RYR1 variants in patients with a previous history of recurrent rhabdomyolysis or those with congenital myopathies without a genetic diagnosis, before administration of triggering anesthetics. Such patients in whom a RYR1 variant is found or indeed patients with a known RYR1-related myopathy should be referred to a specialized MH center for assessment of their MH risk and advice on further investigation.

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