Malignant hyperthermia (MH) is an anesthetic-drug–induced, life-threatening hypermetabolic syndrome caused by abnormal calcium regulation in skeletal muscle. Often inherited as an autosomal dominant trait, MH has linkage to 30 different mutations in the RYR1 gene, which encodes a calcium-release–channel protein found in the sarcoplasmic reticulum membrane in skeletal muscle. All published RYR1 mutations exclusively represent single-nucleotide changes. The present report documents, in exon 44 of RYR1 in two unrelated, MH-susceptible families, a 3-bp deletion that results in deletion of a conserved glutamic acid at position 2347. This is the first deletion, in RYR1, found to be associated with MH susceptibility. MH susceptibility was confirmed among some family members by in vitro diagnostic pharmacological contracture testing of biopsied skeletal muscle. Although a single-amino-acid deletion appears to be a subtle change in the protein, the deletion of Glu2347 from RYR1 produces an unusually large electrically evoked contraction tension in MH-positive individuals, suggesting that this deletion produces an alteration in skeletal-muscle calcium regulation, even in the absence of pharmacological agents.

https://www.cell.com/ajhg/pdf/S0002-9297(07)61459-1.pdf

Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype.

Malignant hyperthermia (MH) is a rare, potentially lethal, clinically and genetically heterogeneous pharmacogenic myopathy, which during or after general anesthesia manifests as MH crisis (MHC) in genetically predisposed, but otherwise mostly normal, individuals (MH susceptibles) in response to anesthetic-triggering agents. MHC can also occur in patients with central core disease. MCH-like crises have been reported in those with Duchenne/Becker muscular dystrophy, myotonic dystrophy, mitochondriopathy, and various other conditions. MH susceptibility is diagnosed if there is an MHC in the individual or family history or by the in vitro caffeine-halothane contracture test. Although screening for mutations in the ryanodine-receptor-1 gene and the dihydropyridine-receptor gene, respectively, could further substantiate the diagnosis, the caffeine-halothane-contracture test still remains the gold standard for diagnosing MH susceptibility. The most well-known triggers of an MHC are depolarizing muscle relaxants and volatile anesthetics. Therapy of an MHC comprises discontinuation of triggering agents, oxygenation, and correction of the acidosis and electrolyte disturbances, treatment of arrhythmias, cooling, and dantrolene. If MH susceptibility is not known preoperatively and an MHC unexpectedly interrupts anesthesia, consultation by a specialist in MH susceptibility after anesthesia is essential to investigate the patient for MH susceptibility or subclinical myopathy, guide laboratory investigations, manage therapy, and counsel the family on further risk. To further reduce morbidity and mortality of those with MHC, anesthesiologists and neurologists should be well educated and should strengthen their clinical vigilance. Research should be intensified and extended with regard to the development of new in vitro tests to further elucidate the heterogeneous genetic background of MH susceptibility.

Current concepts in malignant hyperthermia.

Malignant hyperthermia (MH) is a metabolic myopathy with an abnormal release of calcium by the sarcoplasmic reticulum (SR), triggered by volatile anesthetics and succinylcholine. Similarly, caffeine enhances Ca(2+)release by the SR in vitro. In a prospective, randomized study, high-energy phosphates were studied by intramuscular 31-phosphorus magnetic resonance spectroscopy ((31)P-MRS) in 10 MH-susceptible (MHS) and 7 MH-nonsusceptible (MHN) subjects before and after injection of 0.5 ml caffeine (20 mM). Intramuscular energy balance, measured by the ratios of P(i)/PCr and P(i)/gamma-ATP, did not differ between MHS and MHN patients before and after intramuscular caffeine injection. However, within each group, P(i)/PCr and P(i)/gamma-ATP increased significantly only in the MHS group. Intramuscular caffeine injection seemed to impair the metabolic balance in MHS individuals. This may reflect a local calcium overload leading to consumption of high-energy phosphates and increase of inorganic phosphate. Intramuscular stimulation by caffeine and (31)P-MRS may provide a valuable tool to investigate MH-related metabolic disturbances.

Caffeine impairs intramuscular energy balance in patients susceptible to malignant hyperthermia

Effect of Halothane on the Oligomerization of the Sarcoplasmic Reticulum Ca2+-ATPase

Introduction

Malignant hyperthermia (MH) is a potentially lethal anesthesic complication. Pathological symptoms develop after exposure to triggering substances. It remains uncertain whether cellular alterations pre-exist. Mechanical properties of isolated muscle bundles were examined before and after exposure to a triggering substance.



Methods

With prior written consent, muscle bundles of 12 MH-susceptible (MHS) and 56 MH-nonsusceptible (MHN) individuals were examined before and after exposure to incremental doses of caffeine. Mechanical properties (baseline tension, peak tension, time to peak tension, and relaxation time) were measured. Contraction and relaxation derivatives and contraction–relaxation coupling were calculated and analyzed.



Results

Mechanical properties were not different between the groups before caffeine application. Caffeine increased peak tension in both groups and baseline tension only in MHS muscle bundles; relaxation time/derivative and contraction–relaxation coupling were prolonged.



Conclusions

Cellular changes seen in MH are not pre-existing. Exposure to triggering substance impairs relaxation in MHS muscle. Muscle Nerve 52: 580–583, 2015

Effect of caffeine on intrinsic mechanical properties of normal and malignant hyperthermia-susceptible muscle.

The purpose of this investigation was to compare the effects of halothane on malignant hyperthermia (MH) and normal isolated muscle bundle performance during isometric contraction and relaxation phases. Mechanical parameters were measured: peak tension (PT), time to peak tension (TPT) and positive peak of isometric tension derivative (+dP/dt max) characterized the contraction phase. Half-relaxation time (RT 1/2) and negative peak of isometric tension derivative (-dP/dt max) characterized the relaxation phase. The ratio R= (+dP/dt max) /(-dP/dt max) was used to study the coupling between contraction and relaxation under isometric condition. In normal muscle, halothane increased PT by nearly 40% without altering TPT. The +dP/dt max value increased concomitantly with the -dP/dt max values, thus no changes in R was observed. In MH muscle, PT was first potentiated (0.5-1.0 vol% halothane) and then depressed (2.0–3.0 vol% halothane). TPT and +dP/dt max were not altered whereas RT 1/2 increased progressively wit...

Effects of halothane on mechanical response of skeletal muscle from malignant hyperthermia susceptible patients.

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Effects of halothane on mechanical response of skeletal muscle from malignant hyperthermia susceptible patients.