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Contempo Updates | Clinician's Corner

Malignant Hyperthermia:  Update on Susceptibility Testing

Ronald S. Litman, DO; Henry Rosenberg, MD, CPE
JAMA. 2005;293(23):2918-2924. doi:10.1001/jama.293.23.2918.
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Quiz Ref IDMalignant hyperthermia (MH) is a pharmacogenetic clinical syndrome that manifests as a hypermetabolic crisis when a susceptible individual is exposed to an anesthetic triggering agent. Clinical signs include unexplained elevation of end-tidal carbon dioxide, muscle rigidity, acidosis, tachycardia, tachypnea, hyperthermia, and evidence of rhabdomyolysis. This process is a result of an abnormally increased release of calcium from the sarcoplasmic reticulum, which is often caused by an inherited mutation in the gene for the ryanodine receptor (RYR1) that resides in the membrane of the sarcoplasmic reticulum. The gold standard for determination of MH susceptibility is the caffeine-halothane contracture test. However, it is invasive, requiring skeletal muscle biopsy and is not widely available. Researchers have begun to map mutations within the ryanodine receptor gene (chromosome 19q13.1) responsible for conferring MH susceptibility. Ryanodine receptor mutations are found in at least 25% of known MH susceptible individuals in North America. Mutation analysis has recently become available in the United States and is expected to play an integral role in the diagnosis of MH susceptibility in the future.

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Figure 1. Pathophysiology of Acute Malignant Hyperthermia
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Exposure of an individual who has a genetic susceptibility (ryanodine receptor [RYR1 ] or dihydropyridine receptor [DHP ] mutation) to an anesthetic triggering agent (ie, volatile inhalational anesthetic agent, succinylcholine, or both) may result in malignant hyperthermia. This reaction is caused by an altered calcium balance between the lumen of the sarcoplasmic reticulum (SR) and the sarcoplasm. Normally, muscle cell depolarization is sensed by the DHP receptor, which is thought to signal RYR1 opening by a direct physical connection. In malignant hyperthermia, accumulation of abnormally high levels of calcium in the sarcoplasm causes uncontrolled anaerobic and aerobic metabolism and sustained muscle cell contraction. This results in the clinical manifestations of respiratory acidosis, metabolic acidosis, muscle rigidity, and hyperthermia. If the process continues unabated, adenosine triphosphate (ATP) depletion eventually causes widespread muscle fiber hypoxia (cell death, rhabdomyolysis), which manifests clinically as hyperkalemia and myoglobinuria and an increase in creatine kinase. Dantrolene sodium binds to RYR1, causing it to favor the closed state, thereby reversing the uninhibited flow of calcium into the sarcoplasm.

Figure 2. Algorithm for Sequence of Malignant Hyperthermia Susceptibility Testing
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Once a proband has been determined to be susceptible to malignant hyperthermia (MH) by a clinical episode plus either a positive caffeine-halothane contracture test (CHCT) result or a mutation found on ryanodine receptor (RYR1) sequence analysis, first-degree relatives may be tested, with continued testing of the family until negative results are obtained. Those with the mutation are considered MH susceptible without having to undergo CHCT. Relatives without the mutation should undergo CHCT. *Since CHCT requires muscle biopsy, available in a limited number of centers, some patients may initially elect mutation screening, which involves only blood testing. However, because of its relatively low sensitivity (up to 25%), a negative mutation screen does not rule out MH susceptibility, and CHCT is then recommended for final diagnosis. The sensitivity of RYR1 genetic analysis is higher if the patient selection criteria are based on CHCT rather than clinical episode. If a mutation analysis is performed based on only a clinically suspected MH episode, the clinical episode should be evaluated by 1 or more MH experts to evaluate the likelihood of the episode being MH.
†Probands and their relatives with a positive CHCT and negative mutation analysis should undergo repeat mutation analysis when additional mutations are identified and gene screens become more comprehensive.

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