Genetic analysis of three families in New Zealand was used to show two genetic mutations that were associated with malignant hyperthermia. (Image source: Thinkstock)

Genetic analysis of three families in New Zealand was used to show two genetic mutations that were associated with malignant hyperthermia. (Image source: Thinkstock)

Three patients from three families had similar anesthetics with similar outcomes: succinylcholine and in two also, halothane. The ensuing three malignant hyperthermia (MH) reactions were assessed and characterized by CGS score as “almost certain,” “very likely,” and “somewhat less than likely”  After genetic analysis, family trees were generated to show which relatives were malignant hyperthermia susceptible based on DNA testing. By considering whether the abnormal genes separated with episodes of malignant hyperthermia in the three families, Dr. Anja H. Schiemann, Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand, and colleagues were able to expand the number of causative mutations shown to be associated with MH in New Zealand families. The results of their work are published in this month’s issue of Anesthesia & Analgesia in the article “Functional Characterization of 2 Known Ryanodine Receptor Mutations Causing Malignant Hyperthermia.”

In two families, a R2355W change (RYR1 amino acid change from arginine to tryptophan at position 2355) was identified and in one family, a V2354M change (RYR1 amino acid change from valine to methionine at position 2354) was identified.  DNA screening in more than 100 MH negative individuals did not detect either variant. When bioinformatic tools were used to predict how the mutations would affect protein function, both variants had a damaging impact on protein function.  Calcium release assays showed that the mutations increased sensitivity to 4-chloro-m-cresol.

The R2355W variant has been identified in other families in the UK and US. As the authors note, this variant can be considered a causative mutation for MH. The same is not yet true for the V2354M variant.  As Dr. Jerome Parness, Department of Anesthesiology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, notes in the accompanying editorial, “Hot on the Trail of ‘I know it when I see it!’”, of the more than 300 variants in ryr1 that have been identified, only 31 are known to be causative. Even if genetic analysis is negative, there may well be causative genes not yet identified. All of this is complicated by the fact that MH is a spectrum, and sometimes the diagnosis is uncertain.

In the three patients, succinylcholine was used as part of an anesthetic. Given that genetic analysis is expensive and not yet readily available before an anesthetic, the study, though interesting, should also make one pause before routinely using succinylcholine to facilitate the endotracheal intubation lest the case serve as the basis for another analysis of an MH variant.