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

Mh, a Pharmacogenetic Disorder

MH susceptibility is commonly stated to be a monogenic disorder with locus and allelic heterogeneity. The prevalence of the genetic trait has been estimated to be between 1:2,000 and 1:3,000.[20] Interestingly, the combined prevalence in the ExAC Browser database (http://exac.broadinstitute.org/gene/ENSG00000196218; accessed April 2, 2017) of functionally characterized genetic variants that have been associated with MH is 1:2,750. These prevalence rates are considerably greater than the reported incidence of clinical MH episodes,[21] and the discrepancy is interesting to consider. Monnier et al.,[20] suggested that the penetrance of the MH genetic trait was incomplete, which indeed was the genetic model proposed by Denborough et al.[22] when they reported the first case. Incomplete penetrance of a genetic trait implies that the genetic defect either requires additional factors for the phenotype to occur or other factors can prevent the occurrence of the phenotype. It is recognized that the lack of penetrance of the clinical MH phenotype can be for nongenetic reasons, because some people who develop MH are known to have had previous exposure to triggering anesthetics with no apparent problem. Unlike the Australian family reported by Denborough et al.,[22] however, there are relatively few MH families where the number of clinical episodes is sufficient to draw any inference about the mode of inheritance. In most families, evidence of a dominant pattern of inheritance is derived from results of laboratory testing using pharmacologic challenge of excised skeletal muscle strips in an in vitro contracture test. These tests are known as the caffeine–halothane contracture test in North America and the in vitro contracture test in Europe. However, because these tests are invasive and costly, family studies are limited in some countries, whereas in others the testing strategy assumes an autosomal dominant pattern of inheritance with an inevitable bias in the resultant family structure.

Lack of penetrance of a genetic trait may also arise for genetic reasons with defects in more than one gene operating together to produce a phenotype or indeed opposing each other to modify or even obscure a phenotype. There is reproducible evidence for the presence of more than one genetic factor influencing the MH susceptibility phenotype,[23] leading Carpenter et al.[24] to propose a threshold genetic model for MH susceptibility. Such a model, in which the relatively weak pathogenic effect of the more prevalent MH–associated variants is subject to modifying effects of other genetic variants, provides a compelling explanation for the apparent discrepancy between the genetic prevalence and clinical incidence of MH.

RYR1, encoding the ryanodine receptor–Ca2+ release channel of skeletal muscle sarcoplasmic reticulum (RyR1), has been established as the major gene implicated in MH. Since the report[7] of the first human MH–associated RYR1 variant, hundreds of MH probands and thousands of members of their families have been screened for RYR1 variants, and MH–associated variants have been found in more than half of the MH families studied from different populations.[8,25,26] A small number of MH–susceptible families carry a variant in the second MH gene, CACNA1S, encoding the α-1S subunit of the T-tubular voltage-gated Ca2+ channel Cav1.1, also known as the dihydropyridine receptor.[9–11,27] The α-1S subunit is important for the voltage sensing and Ca2+ conduction of the dihydropyridine receptor.

However, up to 50% of MH probands, who survived an MH event and whose MH susceptibility status was confirmed by a positive in vitro contracture test, do not carry any RYR1 or CACNA1S variants, and the genetic basis of their MH susceptibility remains unresolved.[21,27,28] Four additional MH loci have been implicated by linkage analysis in several European and North American families, but no MH–associated gene has been confirmed within those loci yet.[29] Recently, a homozygous STAC3 mutation has been linked to Native American myopathy associated with MH susceptibility in one Native American family.[12] Normal functioning of Stac3 protein, encoded by STAC3, is thought to be required for effective colocation of dihydropyridine receptors and RyR1s.

RyR, dihydropyridine receptor, and Stac3 protein are all essential components of the skeletal muscle excitation–contraction coupling complex.[30] The underlying mechanism of MH is disruption of excitation–contraction coupling resulting in abnormally enhanced Ca2+ release from the sarcoplasmic reticulum via RyR1 in response to either endogenous (e.g., voltage) or exogenous (e.g., halogenated anesthetics) stimuli.

Variants in RYR1 associated with MH susceptibility are heterozygous missense changes that are shown to impact the RyR1 channel function as gain-of-function mutations, making mutant RyR1 channels more sensitive to activation. Functional analysis of the MH–associated CACNA1S variants showed that their effect on excitation–contraction coupling was similar to that shown for RYR1 mutations, i.e., expression of the mutant α-1S in dysgenic myotubes (lacking α-1S) resulted in an enhanced sensitivity of RyR1 to stimuli compared with the effect of wild-type α-1S.[31] It was suggested that α-1S functions as a negative allosteric modulator of RyR1 activation, and the CACNA1S mutations result in suppression of this negative modulatory effect.[2,31,32] Currently, more than 200 RYR1 variants are found in association with MH, but only 35 RYR1 variants and 2 CACNA1S variants are recognized as being sufficiently functionally characterized (http://www.emhg.org; accessed April 8, 2017) to be used in diagnostic genetic testing for MH. Although these variants are frequently referred to as causative mutations, we will refer to them as pathogenic variants because the functional studies demonstrate an effect that is qualitatively consistent with our understanding of MH but, in the context of a possible threshold genetic model, do not prove that the effect would translate into a clinical MH reaction. An individual carrying one of the MH pathogenic variants is considered MH susceptible, i.e., at increased risk of developing MH under anesthesia. When a familial pathogenic variant is identified, genetic testing can be extended to family members, and all members of the family carrying the variant should be considered MH susceptible.[33] However, MH susceptibility cannot be ruled out for individuals who do not carry the familial variant because of the possibility of more than one pathogenic variant being present in the same family,[20,23,34] and they should be offered contracture testing to confirm their MH negative status.[34]

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