Genomic Screening for Malignant Hyperthermia Susceptibility

Abstract and Introduction

Introduction

Malignant hyperthermia (MH) is a syndrome of acutely disordered skeletal muscle excitation–contraction coupling leading to fever, acidosis, hypercapnia, tachycardia, hyperkalemia, muscle rigidity, and rhabdomyolysis that can be triggered by potent inhalation anesthetics and depolarizing neuromuscular blocking agents (e.g., succinylcholine).^[1] An MH reaction is challenging to manage, requiring rapid interventions to halt the procedure, discontinue the triggering agents, administer dantrolene, correct dysrhythmias, and apply other crucial supportive measures.^[2,3] Even though early intervention using these measures is effective in aborting or ameliorating the reaction, the mortality for a malignant hyperthermia reaction is still 4 to 10%.^[4,5] Morbidity is more common, can be severe, and in some cases long lasting (e.g., renal failure). MH susceptibility can be a component of some congenital myopathies but it is most commonly the only manifestation in an affected individual and it is this latter manifestation we are focused on here. MH is a heritable trait, primarily associated with variants in either the type 1 ryanodine receptor (RYR1) intracellular calcium channel or the alpha 1S subunit (CACNA1S) of the voltage-dependent L-type Ca²⁺ channel. The disorder is heritable, but it is not always inherited: rare cases have been shown to be due to de novo mutation events. Another gene associated with MH reactions is STAC3, although all the reported occurrences involve individuals with biallelic variants who have an apparent myopathy: here we are focused on individuals who are asymptomatic until exposed to a triggering agent. A recent report^[6] suggested that TRPV1 is also associated with MH, but this has not been confirmed. Estimates of the prevalence of malignant hyperthermia susceptibility vary widely, from 1/200 to 1/3,000,^[7–9] although the clinical incidence of MH reactions is much lower—between 1:10,000 and 1:150,000 general anesthetics.^[10,11] Of those who have experienced an MHreaction, 50% to greater than 70% are found to have at least 1 of more than 200 variants in either RYR1 or CACNA1S, indicating that there is both locus and allelic heterogeneity.^[1,12]

Research into MH susceptibility over the past decades has provided important insights into the epidemiology, pathophysiology, clinical management, and genetics of this disorder. At the same time, it is recognized that the mortality associated with MH has declined little since the widespread adoption of dantrolene. Given the advancement in scientific understanding and medical management that has occurred, we pose to the field a simple and direct question: what would it take to end deaths from MH?

We are posing this rhetorical question to organize our thinking and direct our clinical and scientific resources toward an ideal objective. The complete elimination of morbidity and mortality from MH is likely impossible since a complete understanding of the biology of this trait, identification of all at-risk individuals, and changing their anesthetic management to the degree needed to drive the mortality to zero is complex. We argue that it is conceivable that we can come close to eradicating all deaths from MH susceptibility or to sufficiently reduce the death rate that the efforts and expenses would be worthwhile. Going forward, MH susceptibility is an attractive target for a genomic screening effort for a number of reasons.

The primary disease manifestation is typically dramatic, severe, and quantifiable.
Most people have almost zero risk of MH, a few people have a high risk, and most of the latter group can be identified.
There is relatively little stigma associated with a diagnosis of MH susceptibility so presymptomatic diagnosis is not highly aversive.
An operating room MH reaction is completely avoidable in known susceptible individuals by avoiding exposure to the triggering agents, which involves decontamination of the anesthetic workstation and use of alternative anesthetics.
Genetic tools with the potential to identify individuals with MH susceptibility are increasingly powerful and costs are falling rapidly.

Here, we outline some ideas about what an organized program to substantially reduce deaths from MH ought to comprise:

Develop a robust and practical physiologic diagnostic test.
Research to identify all genetic loci that cause or contribute to MH susceptibility.
Establish the pathogenicity of all variants in genes that cause or contribute to MH susceptibility.
Develop and pilot genomic screening techniques.
Consultation services to confirm MH susceptibility diagnoses and educate individuals with MH susceptibility.
Healthcare information systems for real-time support and resources for the management of a MH reaction and management of at-risk individuals.

One can readily envision that accomplishing these objectives is feasible and if accomplished, we could reduce the risks of MH at each step of the process from operative planning to discharge. For example, if we can reduce the number of susceptible individuals with who are exposed to a triggering agent by 75% and reduce the mortality rate of an MH reaction by 75%, then deaths from MH would be reduced by more than 90%. This is an exciting and worthy aim, and we outline some important considerations for the unmet objectives below.