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.
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.
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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