What Accounts for the Variability of Expression of Malignant Hyperthermia?

One of the persistent and recurring questions related to Malignant Hyperthermia, as is true for many other disorders, is why the syndrome progresses at different rates in different patients and what accounts for the varied manifestations of MH.  Why for example, do some patients develop MH rapidly and dramatically on the very first exposure to the MH triggering agents while others may require many hours of anesthesia before the early signs of MH appear? And even then the progression of signs of MH may be slow. 

Various explanations have been offered for this observation. To some, the reason relates to the anesthetic itself. That is, some of the MH triggers appear to be “weaker” triggers than other anesthetics. Others have suggested that the reason for the variability relates to the concentration of anesthetic gas that is used during the anesthetic as well as duration of exposure.  Still others believe it is related to the concomitant use of other drugs, especially succinylcholine.  And finally, it has been suggested that the variation may be related to an individual’s genetic predisposition to the syndrome.  In all probability all of these factors play a role, but it is not clear which, if any are more important than others. 

In order to obtain a better understanding of the variability of expression of MH, the study of the effect of genetics, i.e. DNA and mutations in the genes that are causal for MH, is essential.  However, such studies are incomplete without information concerning the phenotype or clinical expression of the syndrome. For that, a large number of  patients with known genetic changes, i.e. DNA changes, as well as information on the clinical expression of the syndrome along with response of muscle to anesthetic exposure (as occurs during muscle biopsy testing for MH) is required. 

Such a study has recently been conducted and published by the MH investigation unit at Saint James’s University Hospital in Leeds, UK (Ref). This unit has perhaps the largest experience of any testing center in the world with muscle biopsy testing, genetic results and clinical features.  The study, which was published in the British Journal of Anaesthesia, demonstrates that specific mutations do influence the clinical expression of the MH syndrome in a meaningful way, regardless of the anesthetic agent used.   

The investigators chose to use “time to clinical onset of MH” as the index of severity of the clinical syndrome.  The clinical onset, as described by the anesthesiologist in the anesthesia record, was assessed from carbon dioxide elevation, heart rate and body temperature.  They also assessed the baseline (preanesthetic) creatine kinase (CK) level, which is a blood test that measures the integrity of the muscle membrane, that is, the extent of muscle damage or the presence of other muscle disorders.  

This very detailed study examined many correlations between the results of the muscle biopsy contracture test, clinical characteristics of the syndrome and DNA changes in the ryanodine receptor gene (RYR-1). DNA changes in this gene are likely associated with over 70% of cases of MH. 

The findings that I wish to highlight are:

Ø    First, that the increase in muscle tension to test drugs used in the muscle biopsy contracture test was correlated to clinical response time in the OR for the development of MH as well as baseline CK levels.

Ø    Second, certain mutations in the RYR-1 gene were also associated with accentuated contractures of the muscle during contracture testing, rapidity of onset of clinical MH as well as baseline CK levels.  Some of these mutations have previously been shown to lead to increased intracellular calcium release from storage sites in isolated cell systems.  This change is characteristic of cells in MH susceptibles. 

Remarkably, in this study of hundreds of patients there was NO correlation between types of volatile anesthetic gas or the use of succinylcholine with time of onset of the clinical syndrome.  In other words, the clinical expression of MH seems to be more likely to be a result of DNA, i.e. genetic makeup, than drug exposure.  

One of these mutations has turned up in several patients who experienced “non anesthetic induced MH” which is also known as exertional heat stroke and exertional rhabdomyolysis (muscle breakdown). Interestingly, some of the mutations found in the skeletal muscle ryanodine receptor gene are also found in the cardiac ryanodine receptor. This receptor is similar in structure to the ryanodine receptor in skeletal muscle and like that structure is involved in calcium movement in the cell to effect muscle contraction.  In the case of the cardiac cell though, an additional effect is on heart rhythm generation. The rare syndrome of sudden death from a specific cardiac rhythm disturbance has been traced to the cardiac ryanodine receptor and like MH, this syndrome is an inherited disorder (catecholaminergic polymorphic ventricular tachycardia). 

What are some of the implications of this study?  They are many and varied, but here are a few.

Ø   If a patient who develops MH is found to have one of the mutations associated with rapid onset of MH, perhaps s/he will need more aggressive dantrolene therapy to prevent a recrudescence of the syndrome.

Ø   Secondly, some patients with unexplained CK elevation should be evaluated by genetic testing for MH susceptibility.

Ø    Third, patients who experience exertional heat stroke should have multiple CK determinations, and if the level fails to return to normal, a detailed anesthetic family history should be obtained and consideration given to DNA testing for MH related mutations. 

The European MH group recommends that genetic testing only be performed following the halothane caffeine contracture test for MH. That policy is not practical for North America because of the limited number of MH biopsy centers and restrictive reimbursement policies. 

The MH investigators who form the Leeds, UK MH group are to be complimented for their continuing valuable contributions to the understanding of MH and clarification of the clinical characteristics of MH and Central Core Disease (which is also associated with mutations located on the RYR-1 gene). 

Reference:

Carpenter D, Robinson RL, Quinnell RJ , Ringrose C, Hogg M, Casson F, Booms P, Iles DE, Halsall PJ, Steele DS, Shaw MA and Hopkins PM.Genetic variation in RYR1 and malignant hyperthermia phenotypes.

British Journal of Anaesthesia July 31, 2009.  

Click on below link for abstract.