SCIENTIFIC BACKGROUND

CACNA1S, RYR1

Scientific Background

Malignant hyperthermia (MH) is a genetically caused Ca2+ regulatory disorder of the skeletal muscles. In genetically predisposed individuals, the administration of volatile anaesthetics (fluranes) and depolarising muscle relaxants (e.g., suxamethasone) can lead to a potentially life-threatening hypermetabolism. The symptoms are very variable and range from moderate forms with low severity to a fulminant MH crisis. In the early phase, classic signs of a fulminant MH crisis are tachycardia, hypercapnia, hypoxemia and masseter spasms; in the late phase, acidosis, hyperkalemia, rhabdomyolysis and hyperthermia are added. The antidote dantrolene has reduced the mortality rate in MH crises to <5%. The prevalence of MH in the German population is estimated at 1:10,000. The incidence of a fulminant MH crisis is about 1:60.000. In predisposed patients the administration of trigger substances must be avoided. Without trigger substances there is usually an unapparent myopathy.

 

Pathogenic variants in the ryanodine receptor 1 (RYR1) and the dihydropyridine receptor (voltage-dependent L-type calcium channel, CACNA1S) are associated with a predisposition for MH. Heredity is autosomal dominant with incomplete penetrance. Variants in one of these genes could be identified in about 75% of MH families. The detection of a causative variant enables the identification of other relatives at risk by means of target diagnostics. However, so far only about 50 variants have been categorized as causative by the European Malignant Hyperthermia Group (EMHG). In addition, the studies did not identify variants in the RYR1 or CACNA1S gene in all affected patients, so that a negative molecular genetic finding does not rule out the presence of MH. Therefore, where suspicion exists and there are negative genetic findings or if variants of unclear significance are detected, an in vitro muscle contraction test (IVCT) should be performed to confirm the diagnosis.

 

References

Gonsalves et al. 2019, Clin Pharmacol Ther 105:1338

GENES

CACNA1S, RYR1

ASSOCIATED TESTS

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