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 Metabolic Disorder

Because RyR1 plays an essential role in maintenance of Ca2+ homeostasis and in excitation–contraction coupling in skeletal muscle cells,[2] MH–susceptible individuals carrying RYR1 variants may have skeletal muscle metabolism abnormalities even in the absence of triggering anesthetics.[97,98] Studies on animal models of MH[51,99,100] have shown that MH–associated RYR1 variants result in a significant increase in mitochondrial matrix Ca2+, increased reactive oxygen species production, and lower expression of mitochondrial proteins, which in conjunction with lower myoglobin and glycogen contents and lower glucose utilization suggested a compromised bioenergetics state. Furthermore, the elevation in resting myoplasmic Ca2+ may lead to an enhanced oxidation of RyR1, which in turn may increase open channel probability, enhanced Ca2+-induced Ca2+ release,[101] thus increasing muscle sensitivity to heat and other stimuli.[102] Such studies might explain the connection between MH and exertional rhabdomyolysis (ER) and/or exercise-related or exertional heat illness (EHI). The most severe form of EHI, exertional heat stroke (EHS), is characterized by a rapid increase in body temperature and neurologic impairment, with rhabdomyolysis as a common feature.[75,103] It occurs during sustained exercise frequently in physically fit young adults and children, especially under hot or/and humid ambient conditions but it may occur in temperate climates.[16,34,104]

ER often presents with severe muscle pain and is diagnosed by elevated serum creatine kinase levels five times higher than the upper limit of normal values.[16,103] ER is one of the frequent signs of EHI but often does not involve a drastic increase in body temperature. EHS and MH share clinical features such as hyperthermia, muscle rigidity, tachycardia, tachypnea, elevated serum creatine kinase, and disseminated intravascular coagulation; and skeletal muscle breakdown may cause hyperkalemia, myoglobinuria, and acute kidney injury. On the basis of abnormal in vitro contracture test results in survivors of EHS and their first degree relatives, it was postulated that there may be a familial skeletal muscle abnormality in some EHS patients similar to that in MH, i.e., uncontrolled increase in intracellular calcium and hypermetabolism.[105]

Dantrolene, the only drug available for treating MH, has been shown to reduce clinical symptoms in patients with ER[74] supporting a notion of a common pathologic pathway of these potentially fatal conditions.

Recurrent ER as an inherited condition has been linked to defects in the genes known to be associated with a number of neuromuscular disorders, such as metabolic myopathies and muscular dystrophies, many of which are autosomal-recessive or X-linked.[106,107]

Recent genetic studies have suggested that RYR1 variants may be implicated in EHI/ER.[16,17] Moreover, identification of MH–associated RYR1 variants in up to 30% of cases of recurrent ER[16,98,108–110] has strengthened the possibility of a link between MH and EHI/ER. This possible link, important to MH researchers, clinicians, and especially patients with MHS and EHI, has been discussed in several publications.[16,103,111] We have considered two questions in summarizing the clinical and genetic evidence regarding the relationship between MH and EHI/ER.

The First Question: Are MH–susceptible Patients at a Higher Risk of EHI/ER?

Based on the clinical data available on MH–susceptible patients, there seems to be no strong correlation between MH susceptibility and predisposition to EHI. There are numerous MH families with at least one family member who survived an MH crisis under general anesthesia. Hundreds of individuals from these families have been diagnosed as MH susceptible by the in vitro contracture testing and additionally have been found to carry one of the known MH pathogenic variants.[112] These MH–susceptible individuals show no apparent predisposition to EHI and are reported to be clinically healthy.[2,8] Moreover, none of the MH–susceptible individuals who are homozygous for MH pathogenic variants: p.Arg614Cys, the analog of the p.Arg615Cys porcine stress syndrome mutation,[20,113–115] and p.Cys35Arg,[116] nor individuals who are compound heterozygous for two MH variants have been reported to present with any clinical symptoms suggestive of EHI.[8,20,26,115] Indeed, there have been only a few documented cases of patients with a previous personal or family history of MH who later in life experienced an EHS/EHI episode.[103,109,117,118] There is perhaps a greater risk of MH–susceptible individuals developing ER than EHI. In addition to reported cases,[17] the authors have been contacted by several patients tested MH susceptible in their units who have developed ER. Nevertheless, these observations do not support a notion of all MH–susceptible patients being at an increased risk of EHI/ER.

The Second Question: Are EHI/ER Patients at Risk of MH?

The notion that EHI patients may be predisposed to MH mostly stems from the reports of positive in vitro contracture testing results, i.e., MHS diagnoses in a substantial number of EHI patients.[18,35,98,105,108,119–121] It is important to emphasize that the in vitro contracture tests have been validated only for patients with a suspected anesthetic-induced MH reaction, and the sensitivity and specificity of the in vitro contracture testing in patients with EHI/ER are unknown. Patients with certain myopathies, such as muscular dystrophies and muscle channelopathies, may have abnormal in vitro contracture test results due to their persistent muscle cell abnormalities not necessarily related to MH.[122–124]

The genetic connection between EHI/ER and MH also remains inconclusive.[17,19,34,97,120] An increasing number of reported EHI/ER cases with MH–associated RYR1 variants favor this connection, and undoubtedly, EHI/ER patients carrying MH–associated variants should be considered MH susceptible until demonstrated otherwise. However, in more than 70% of the EHI/ER patients, the identified RYR1 variants are rare variants of unknown functional significance.[16,34,110] The relevance of these variants of unknown significance to either MH susceptibility or EHI/ER remains unclear, especially considering some rare, potentially deleterious variants of unknown significance have been identified in EHI patients who have had normal in vitro contracture responses, whereas others are found in EHI patients with abnormal in vitro contracture responses. Remarkably, among the numerous EHI/ER cases with identified RYR1 variants, there have been no reports of personal or familial history of MH; only one episode of MH in a patient who had a previous ER event has been reported so far.[74]

Thus, although current studies cannot rule out a possible connection between MH and EHI/ER, the extent of the overlap between EHI/ER and MH remains unknown. Both conditions have a complex etiology and in the majority of cases probably result from the interplay between genetic and environmental factors and indeed, in some cases, possibly multiple genetic factors. Importantly, in patients with ER or EHI differential diagnoses, such as muscular dystrophies and metabolic and mitochondrial disorders, should be considered. To make an efficient and definitive diagnosis in a clinically and genetically heterogeneous condition, such as ER, targeted parallel sequencing of a panel of candidate genes using next-generation sequencing seems to be an especially appropriate approach. Currently some laboratories offer screening of panels of genes using next-generation sequencing technologies for patients with myopathy/rhabdomyolysis; some of those in North America are Baylor Miraca Genetics Laboratories, Baylor College of Medicine (USA), PreventionGenetics (USA), and Fulgent Therapeutics LLC (USA).

The existence of a possible link between ER and disorders of muscle calcium metabolism warrant an expansion of the next-generation sequencing gene panel for myopathy/rhabdomyolysis to include the genes involved in excitation–contracture coupling, such as RYR1 and CACNA1S. Indeed, several centers have already included the RYR1 gene in their expanded panels, e.g., next-generation sequencing rhabdomyolysis and metabolic myopathies panel (Greenwood Genetic Center Diagnostic Laboratories, USA) and metabolic myopathy and rhabdomyolysis panel (Blueprint Genetics, Finland).

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