Genomic screening of susceptibility to malignant hyperthermia

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Genomic screening of susceptibility to malignant hyperthermia

Genomic screening of susceptibility to malignant hyperthermia.  It is currently impossible to completely eliminate the morbidity and mortality of MH, but preoperative MH susceptibility screening provides evidence of pre-symptomatic diagnosis.

Malignant Hyperthermia (MH) is a syndrome of severe disturbance of skeletal muscle excitation-contraction coupling caused by inhaled anesthetics and depolarizing muscle relaxants (such as succinylcholine), accompanied by fever, acidosis, and hyperthermia.

Symptoms of capnia, tachycardia, hyperkalemia, muscle stiffness, and rhabdomyolysis. The incidence of malignant hyperthermia (MH) associated with general anesthesia is very low (1:10000 to 1/150000), but the mortality rate is high (4% to 10%).

Once it happens, you need to stop the trigger immediately, use dantrolene, correct the arrhythmia, and give corresponding supportive treatment. But these early interventions did not reduce the mortality rate of MH.

This issue brings a review in “Anesthesiology” magazine, discussing the potential to eradicate or significantly reduce related deaths based on MH susceptibility.

It is very likely that it will not be possible to completely eliminate MH, because it is complicated to fully understand the biological characteristics of MH, identify all high-risk individuals, and change their anesthesia management to the extent necessary to reduce mortality to zero. It is conceivable that we can approach the eradication of all MH-susceptible deaths, or fully reduce the mortality rate. Such efforts and expenses are worthwhile.

Looking ahead, MH susceptibility is an attractive target for genome screening for several reasons.

1. The main clinical manifestations of the disease are usually very serious and can be quantified;
2. The risk of MH in most individuals is almost zero, and a small number of high-risk individuals can be determined;
3. The diagnosis of MH susceptibility is unlikely to arouse disgust or resistance from the parties concerned;
4. For people who are known to be susceptible, avoiding contact with triggers can completely avoid MH;
5. The cost of genetic screening for MH-susceptible individuals has dropped significantly.

MH is a genetic disease, which is mainly related to the variation of the intracellular calcium channel of type 1 ryanodine receptor (RYR1) or the α1S subunit (CACNA1S) of the voltage-dependent L-type calcium channel, and the STAC3 gene is also related to it. Among individuals with MH, more than 50%-70% have at least one variant among more than 200 variants of RYR1 or CACNA1S, which indicates the existence of locus and allele heterogeneity.

Susceptibility refers to the risk of an individual determined by the genetic basis of disease. Susceptibility to MH may be part of some congenital myopathy, but it is usually the only manifestation of affected individuals. Although all currently reported cases involve individuals with obvious biallelic variants of myopathy, this article focuses on the latter, focusing on individuals who were asymptomatic before exposure to the trigger. Research on susceptibility to MH in the past few decades has provided important insights into the epidemiology, pathophysiology, clinical treatment and genetics of the disease. At the same time, it was found that the widespread use of dantrolene hardly reduced MH-related mortality.

Given the advances in scientific cognition and medical management, how can we end the deaths caused by MH?

1. Develop accurate and practical physiological diagnostic tests

Accurate phenotypic analysis is essential in genetic research. The clinical manifestations of MH can be identified at the initial stage, and rarely develop to the fulminant stage with a clear diagnosis. Although the diagnosis can be made based on the clinical response of the primary patient, it is difficult to determine the clinical phenotype of other family members.

The progress of MH genetics is essentially based on the use of MH susceptibility phenotypes determined by (muscle) contracture tests. However, for some reasons, contracture tests cannot be universally implemented, and alternative clinical phenotypic tests have not yet been developed. Therefore, the development of an accurate and practical physiological diagnostic test will greatly improve the usability of MH detection.

2. Research to identify all gene loci that cause or contribute to MH susceptibility

Genome technology is developing rapidly, mainly due to chip-based DNA testing platforms and next-generation sequencing technologies. The cost of next-generation sequencing is much lower than that of Sanger sequencing of RYR1 and CACNA1S, which enables both research and clinical genomic testing. However, there may be thousands of these variants in each sample, so predicting variants involved in the disease may be difficult. In the susceptibility to MH that may be caused by only one missense variant, once the variants in RYR1, CACNA1S, and STAC3 are excluded, this sequencing method is useless. Currently, samples from MH-susceptible individuals rarely undergo exome or genome sequencing. If more genes can be sequenced, we will be more likely to identify rare recurrence variant genes.

All identification data derived from individuals who have been sequenced and found to contain pathogenic or possibly pathogenic variants should be included in the public repository. Individuals who have not found a clear pathogenic variant should refer to the clinical research plan and further evaluate.

3. Determine the pathogenicity of all gene variants that cause or contribute to MH susceptibility

People are working hard to fully describe the pathogenicity of variants reported in RYR1 and CACNA1S through the ClinGen variant management expert group program (https://www.clinicalgenome.org/affiliation/50038). This work initially focused on the variants proposed by the European MH team, and was adjusted according to the pathogenicity standards of the variants of the American College of Medical Genetics and Genomics. These standards must take into account the biological knowledge and malignant hyperthermia susceptibility of RYR1, including 27 standards such as genetic observation, case-control studies, functional studies and computer predictions.

A major drawback in determining the pathogenic state is that the number of variants with powerful features in the relevant model system is small. Although the current test is stable, the pass rate is low. A recent revolution in functional genomics may overcome this bottleneck in the future. Improved CRISPR technology coupled with high-throughput functional analysis strategies may support highly robust functional evaluation of all variants. If these technologies can be used for RYR1 and other genes related to MH susceptibility, then they may provide high-throughput, low-cost, functional in vitro analysis for each potential variant. Even if only the pathogenicity of the variants that account for 80% of known MH susceptibility cases can be assessed, a set of pathogenic variants that can be used in clinical research will be generated to test the practicality of preoperative screening.

4. Develop and trial genome screening technology

In the future, there will be a large number of individuals undergoing genome-wide screening covering genetic susceptibility to many diseases and drugs. Once the pathogenic variants are identified, the individuals undergoing elective surgery can be screened for MH susceptibility. The scale and power analysis of such studies require a more accurate assessment of the prevalence and diagnosis rate of a specific set of pathogenic variants.

Although the general population’s MH susceptibility screening cannot be achieved in a short time, more and more individuals with RYR1 and CACNA1S variants are being discovered through the secondary detection of exome and genome sequencing. This variant is It is the only known risk factor for MH susceptibility in the family. In such families, the risk of MH (50% for first-degree relatives) is greater than that of the general population. Therefore, a prospective determination of relative risk can be performed by detecting a single variant.

5. Provide MH susceptibility diagnosis consultation services and educate MH susceptible individuals

It is not enough for susceptible individuals to undergo genetic testing and physiological confirmation. They also need the help of an anesthesiologist, neurologist, or clinical geneticist to analyze test results and perform clinical molecular diagnosis, and provide medical advice to patients and their families Nursing staff are educated about their diseases. The patient is the key, they must accept and understand the diagnosis and its meaning, and make the most of the information to help themselves.

Professional institutions (such as the American Association of Anesthesiologists) need to develop policies and practice standards based on the risk stratification of genomic predictive testing. In obstetrics, prenatal non-invasive genome screening tests have been carried out quickly, with clear guidelines and risk determination methods. Such guidelines cannot completely avoid liability, but it can greatly reduce risks.

6. The medical and health information system provides real-time support for the management of MH and high-risk groups

In North America, the American MH Association provides round-the-clock hotline support for clinicians who treat known or suspected MH patients (similar resources are available in other countries). These valuable resources should be universally recognized and easy to use, but more resources should be developed for MH identification and management. Artificial intelligence-driven patient monitoring and clinical decision support tools in electronic health records can be developed to support preoperative decision-making on test results and promote real-time early identification of MH. Finally, information about susceptibility to MH should be easy to carry so that patients can benefit from it no matter where they receive treatment

Conclusion

The above-mentioned research, screening, education and management methods should be integrated into a comprehensive system to end the deaths caused by MH. The focus of this article is to study the susceptibility of MH with genomics as the center.

Major disruptive developments in muscle physiological testing may completely change this evaluation method. The author proposes a model as shown in Figure 1 in order to establish data and experience for the future.  Hope that in the future, more colleagues will join hands and work towards the goal of ending MH-related deaths.

Figure 1. Model for managing MH susceptibility risk through genome screening.

The blue box indicates the current method for determining the phenotype of MH susceptibility, in which contracture test and DNA test are not applicable; the purple box indicates the proposed future method, which supplements the current method. “Abnormal testing” means that there are mutations that may cause susceptibility to MH, while “Not abnormal testing” results in the opposite.
Boxes with * indicate steps that should be considered for contracture testing to assess the risk of MH.

Exprt Comments:

MH is a family-hereditary subclinical muscle disease, which is mainly triggered by inhaled anesthetics or succinylcholine in an abnormally high metabolic state of skeletal muscle. MH is clinically rare, and once susceptible people develop the disease, the disease progresses rapidly. The current diagnosis of MH mainly includes clinical diagnosis, in vitro skeletal muscle contraction test and genetic diagnosis.

By quickly identifying the sequence variants that may occur in individuals with MH, the author of this article emphasizes methods to reduce MH-related deaths from the perspective of genome screening, and recommends that clinical researchers make full use of the system coordination network to increase the chances of identifying pathogenic variants, thereby In perioperative management, it is possible to reduce MH-related deaths the most.

Of course, it is currently impossible to completely eliminate the morbidity and mortality of MH, but preoperative MH susceptibility screening provides evidence of pre-symptomatic diagnosis. Based on these evidences, individuals who are susceptible to MH can be identified, especially individuals who have no suspected family history of MH, which helps clinicians reduce the risk of MH in every step from the patient’s admission, surgery to discharge.

Of course, population genetic disease screening may have false positive and false negative results. False positive results will cause individuals to receive unnecessary non-trigger treatments, and false negatives may lead to rare occurrences of MH. However, improving MH awareness, strengthening MH simulation exercises, preoperative high-risk screening, intraoperative regulatory monitoring, and seeking medical network assistance are important ways to reduce MH-related deaths.

(source:internet, reference only)

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