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Towards a definition and classification of MH and MH-like syndromes

Malignant Hyperthermia (MH) is a life threatening syndrome characterized by hypermetabolism, hyperthermia, acidosis, muscle contraction, muscle membrane breakdown, hyperkalemia and rhabdomyolysis. The syndrome occurs as a result of exposure to certain drugs and /or environmental conditions.  All the signs of MH may appear together or in some combination. The onset and course of the syndrome is variable as well. The underlying cause of MH is thought to be an abnormal, uncontrolled, elevation of intracellular calcium in skeletal muscle cells. Dantrolene sodium effectively reverses the syndrome by restoring calcium levels in the cell toward normal(1). 

Because there are may be many causes of elevated intracellular calcium, and since there are a variety of clinical presentations of MH and conditions that resemble MH (MH-like syndromes), I suggest sub typing the expression of MH and MH like syndromes.

This classification is meant to serve as a framework for thinking about different clinical situations that are often lumped together under the name Malignant Hyperthermia. What follows is my extrapolation  from experimental data and clinical studies. 

MH related to anesthesia

I believe that this is the most common form of MH. Based on sequencing of the DNA of the ryanodine receptor gene (RYR-1), 60-70% of patients who develop MH upon exposure to potent inhalation agents and /or the paralyzing drug succinylcholine will be found to have a mutation in this gene.   However, only about 30% of these mutations have been proven to be causal for the MH syndrome(1), as most of the others have not yet been functionally evaluated.   In about 2% of the MH susceptible population a mutation is found in another gene, the dihydropyridine ( DHPR) gene(2).  Both the RYR-1 and the DHPR gene mutations result in a structural and /or functional change in ryanodine receptor calcium channel activity that promotes increased calcium release from the storage site for this ion in the cell, (the sarcoplasmic reticulum,) and probably increased calcium entry into the cell upon exposure to the agents mentioned above.  

In addition, two muscle disorders (myopathies) characterized by muscle weakness, Central Core Disease and Multiminicore Disease, have as their basis mutations in the RYR-1 gene (see the section on myopathies and MH) and predispose most of these patients to MH. 

MH signs unrelated to anesthetic agents with abnormal RYR 1/DHPR genes

Patients with mutations in the RYR-1 gene may also present with the signs and symptoms of MH when exposed to drugs and environmental conditions that produce elevated intracellular calcium levels other than inhalation agents/succinylcholine.  In animals who are MH susceptible and also have RYR-1 mutations elevated temperature leads to increased calcium release from the sarcoplasmic reticulum stimulates the enzymatic induction of compounds called reactive nitroso intermediates. These compounds, in turn alter the mutated ryanodine receptor resulting in uncontrolled calcium release, muscle contraction, increased heat production and  a vicious “feed-forward” cycle of more calcium in the cell, increased production of reactive intermediates resulting in all the signs of MH(4).

Exercise and muscle exertion may also precipitate muscle breakdown and even clinical MH(5). This has been demonstrated in MH susceptible pigs and in genetically engineered mice that harbor a causal MH mutation in the RYR-1 gene(6) but the pathophysiology remains unknown.  

Statins, free fatty acids, caffeine, serotonin and MDMA agonists also   promote abnormal calcium release from the SR in isolated muscle and sarcoplasmic reticulum preparations with RYR-1 containing MH mutations (7-12).  With sufficiently high concentrations and in combination, these agents may induce sufficiently elevated intracellular calcium to precipitate an MH crisis.  

The Neurolept Malignant Syndrome (NMS) is a syndrome precipitated by a variety of agents that are used to treat psychiatric disorders.  In a few patients who developed NMS an MH-causative RYR-1 mutation has been identified (13) but others do not seem to have such mutations. 

In a few patients an apparent MH crisis has occurred without exposure to anesthetic trigger agents or the drugs mentioned above. The  circumstances that “trigger” the syndrome remain to be clarified.(14).

MH with normal RYR-1 gene.

Elevated intracellular calcium may occur without apparent structural change in the ryanodine receptor as well.   For example,  exposure to a combination of several calcium releasing agents (mentioned above) that individually do not  lead to high enough calcium concentrations to initiate the biochemical changes of MH may result in calcium levels high enough to produce signs of an MH-like syndrome.  This has been demonstrated in pre-clinical animal studies and likely in humans (15,16,17).  

MH due to absence/reduction of Calcium binding proteins

Yet another potential mechanism for elevated intramyoplasmic calcium is the absence or reduction of proteins that buffer the concentration of calcium in the sarcoplasmic reticulum. In the absence of such buffering proteins, such as calsequestrin, marked elevation of intracellular calcium sufficient to cause signs of MH may occur when the muscle is exposed to agents that cause calcium release from the sarcoplasmic reticulum.

This phenomenon has been demonstrated in mice that have been genetically engineered to lack production of calsequestrin (18,19). However, as of now no cases of MH resulting from the absence of these calcium buffering proteins have been reported in humans.

Since mitochondria also play a role in calcium homeostasis in the cell it has been postulated that abnormal mitochondrial function may lead to elevation of intracellular calcium sufficient to induce signs of MH(20). In fact, animals exposed halothane and to the drug 2,4 dinitrophenol that uncouples oxidative phosphorylation will develop signs of MH(21). 

MH and myopathies

Mutations in the RYR-1 gene  are also causal for two muscle disorders , Central Core Disease and Multiminicore disease. The disorders are characterized by weakness and structural changes in the muscle in the absence of anesthesia.  Patients with these disorders are likely to develop MH on exposure to MH trigger agents.(1) 

Certain myopathies not related to mutations in the RYR-1 gene may either directly or indirectly, lead to increased myoplasmic calcium levels upon exposure to calcium releasing agents such as inhalation anesthetic agents. Patients with Duchenne or Becker Muscular Dystrophy display weakness at an early age.  Intracellular calcium is elevated in these patients.  In a mouse model for Duchenne Muscular Dystrophy, Bellinger and colleagues(22) have shown that increased cellular calcium leads to production of reactive nitroso compounds which leads to “leaky” ryanodine receptors as explained above.  Although not directly demonstrated in the mouse model since the animals were not anesthetized  it may be hypothesized that the addition of calcium releasing agents such as halothane or other volatile anesthetics and/or succinylcholine  induce signs similar to those found in MH(22). This might be the mechanism for the well known phenomenon of muscle breakdown, increased serum potassium when some Duchenne Muscular Dystrophy patients are anesthetized with MH trigger agents (23). On the other hand it is not at all clear if dantrolene can reverse these changes.  

This discussion leads to a classification of MH and MH-like syndromes that seek to relate clinical signs to underlying biochemical changes and triggers of MH.  

Subtypes of MH.

For purposes of this discussion, the clinical MH syndrome is defined according to the generally accepted Clinical Grading Scale (24) as likely, very likely and almost certain MH(D4, D5,D6).  For this proposed re-classification of MH and MH-like syndromes, only those subtypes  are termed MH  where the RYR-1 or DHPR gene is mutated . The other subtypes are best described as “MH-like”.

MH Syndromes

Type 1:  Mutations in RYR -1 /DHPR or other genes that are implicated in calcium release from the sarcoplasmic reticulum together with   exposure to volatile anesthetics and /or succinylcholine. That is classical MH.  This might be labeled as Denborough syndrome in recognition of the scientist who first brought the syndrome to the world’s attention.

Mutations in the RYR-1 gene causal for Central Core Disease or MultiMinicore Disease are included in this category.  

Type 2: Mutations in RYR-1 /DHPR or other genes that are implicated in calcium release from the sarcoplasmic reticulum and exposure to non anesthetic drugs/agents or environmental conditions that promote calcium release such as high environmental temperatures. This might be labeled as Britt syndrome in recognition of Dr. Britt’s early work on the description of the syndrome.  

MH-Like Syndromes

Type A. Normal RYR-1 in combination with two or more sarcoplasmic reticulum calcium releasing agents, e.g. caffeine, halothane, heat.

Type B. Normal RYR-1/DHPR and increased calcium due to decrease in sarcoplasmic reticulum calcium buffering proteins

Type C. Normal RYR-1 /DHPR in a patient with a myopathy following exposure to calcium releasing agents.  For example, Duchenne or Becker’s Muscular Dystrophy patients who receive MH trigger agents.


1. Rosenberg H, Davis M, James D, Pollock N, Stowell K. Orphanet Journal of Rare Diseases, 2007 2:21 ( 24 April 2007).http://www.orpha.net/data/patho/GB/uk- malignant-hyperthermia.pdf.

2. Sambuughin N, Holley H, Muldoon , S,Brandom BW, Bantel AM, Tobin JR, Nelson TE, Goldfarb L. Screening of the Entire Ryanodine Receptor Type 1

Coding Region for Sequence Variants Associated with Malignant

Hyperthermia Susceptibility in the North American

Population. Anesthesiology 2005; 102:515–21

3..Carpenter D, Ringrose C, Leo V, MorrisA, Robinson RL, Halsall PJ, Hopkins PM, Shaw MA. The role of CACNA1S in predisposition to  malignant hyperthermia. BMC Medical Genetics 2009,10:104,

4..Durham WJ. Aracena-Parks P. Long C. Rossi AE. Goonasekera SA. Boncompagni S. Galvan DL. Gilman CP. Baker MR. Shirokova N. Protasi F. Dirksen R. Hamilton SL. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knock in mice.Cell. 133(1):53-65, 2008

5.Tobin JR. Jason DR. Challa VR. Nelson TE. Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA. 286(2):168-9, 2001 Jul 11.

6..Trauma, systemic inflammatory response syndrome, dietary supplements, illicit steroid use and a questionable malignant hyperthermia reaction. Capacchione JF. Radimer MC. Sagel JS. Kraus GP. Sambuughin N. Muldoon SM. Anesthesia & Analgesia. 108(3):900-3, 2009 Mar.

7..Exertional rhabdomyolysis and malignant hyperthermia in a patient with ryanodine receptor type 1 gene, L-type calcium channel alpha-1 subunit gene, and calsequestrin-1 gene polymorphisms.

Capacchione JF. Sambuughin N. Bina S. Mulligan LP. Lawson TD. Muldoon SM.

Anesthesiology. 112(1):239-44, 2010 Jan.  

8..Chelu MG. Goonasekera SA. Durham WJ. Tang W. Lueck JD. Riehl J. Pessah IN. Zhang P. Bhattacharjee MB. Dirksen RT. Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in a RyR1 knock-in mouse. FASEB Journal. 20(2):329-30, 2006 Feb.

9..Fletcher JE, Mayerberger S, Tripolitis L, Yudkowsky M, Rosenberg H: Fatty acids markedly lower the threshold for halothane-induced calcium release from the terminal cisternae in human and porcine normal and malignant hyperthermia susceptible skeletal muscle. Life Sciences 49:1651-1657, 1991.

10. Gerbershagen MU. Wappler F. Fiege M. Kolodzie K. Weisshorn R. Szafarczyk W. Kudlik C. Schulte Am Esch J. Effects of a 5HT(2) receptor agonist on anaesthetized pigs susceptible to malignant hyperthermia.British Journal of Anaesthesia. 91(2):281-4, 2003

11. Fiege M. Wappler F. Weisshorn R. Gerbershagen MU. Menge M. Schulte Am Esch J. Induction of malignant hyperthermia in susceptible swine by 3,4-methylenedioxymethamphetamine ("ecstasy").

Anesthesiology. 99(5):1132-6, 2003

12. Guis S. Figarella-Branger D. Mattei JP. Nicoli F. Le Fur Y. Kozak-Ribbens G. Pellissier JF. Cozzone PJ. Amabile N. Bendahan D. In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects.

Arthritis & Rheumatism. 55(4):551-7, 2006

13. Sato T. Nishio H. Iwata M. Kentotsuboi. Tamura A. Miyazaki T. Suzuki K. Postmortem molecular screening for mutations in ryanodine receptor type 1 (RYR1) gene in psychiatric patients suspected of having died of Neuroleptic malignant syndrome.

Forensic Science International. 194(1-3):77-9, 2010

14. Muldoon S, Sambuughin N, Bayarsaikhan M, Dirksen R, Karan, S. A Novel Ryanodine Receptor (RYR1) variant in two children with fatal spontaneous MH like events. Anesthesiology A648, 2008

15.Durbin CG, Rosenberg H:  A laboratory animal model for malignant hyperpyrexia.  J. of   Pharmacology and Experimen­tal Therapeutics 210:70-74, 1979.

16.Storella RJ, Keykhah MM, Rosenberg H: Halothane and temperature interact to increase succinylcholine-induced jaw contracture in the rat. Anesthesiology 79:1261-1265, 1994.

17. Fink E, Brandom BW, Torp KD. Heatstroke in the Super-sized Athlete. Pediatric Emergency Care. 22:510-513,2006

18. Dainese M. Quarta M. Lyfenko AD. Paolini C. Canato M. Reggiani C. Dirksen RT. Protasi F. Anesthetic- and heat-induced sudden death in calsequestrin-1-knockout mice.

FASEB Journal. 23(6):1710-20, 2009

19.Protasi F, Paolini C, Dainese,M. Calsequestrin-1: a new candidate gene for malignant hyperthermia and exertional/environmental heat stroke

J Physiol. 2009 July 1; 587(Pt 13): 3095–3100.

20.Cheah KS, Cheah AM, Fletcher JE, Rosenberg H:  Skeletal muscle mitochondrial respiration of malignant hyperthermia-susceptible patients. Ca2+-induced uncoupling and free fatty acids.  Int J Biochem 21:913-920, 1989. 


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