Malignant Hyperthermia Susceptibility and Genetic Mechanisms

Malignant hyperthermia is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterised by a hypermetabolic response to certain volatile anaesthetics and depolarising muscle relaxants. At its core lies dysregulated intracellular calcium release, primarily through the type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum. Pathogenic variants in RYR1 account for the majority of susceptibility, with additional rare mutations identified in CACNA1S, encoding the CaV1.1 dihydropyridine receptor, which is mechanically coupled to RyR1 during excitation–contraction coupling. Over 400 RYR1 variants have been described, exhibiting variable penetrance and functional impact on channel gating and calcium homeostasis. The resulting hypermetabolism manifests as rapid rises in body temperature, muscle rigidity, lactic acidosis and rhabdomyolysis. Early recognition and prompt administration of the RyR1 antagonist dantrolene have transformed a once often fatal crisis into a treatable emergency. Advances in genetic screening and functional assays have refined diagnostic algorithms, while emerging molecular insights continue to shape risk stratification, therapeutic innovation and peri-operative management globally.

Research from Nature Portfolio

A novel skeletal-muscle-selective RyR1 inhibitor has been developed that both prevents and reverses fulminant malignant hyperthermia and environmental heat stroke in multiple mouse models. The compound offers markedly improved water solubility and rapid in vivo clearance compared with dantrolene, while effectively reducing resting intracellular calcium levels, suppressing anaesthetic-induced calcium release and attenuating caffeine-induced contracture. In vivo administration averted fatal hyperthermic crises under isoflurane anaesthesia and rescued animals subjected to heat stress. This work highlights the therapeutic potential of isoform-selective RyR1 modulation and suggests a new direction for targeted emergency treatments in susceptible individuals.

Malignant Hyperthermia Susceptibility and Genetic Mechanisms publication trend

The graph below shows the total number of articles in malignant hyperthermia susceptibility and genetic mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Malignant hyperthermia (MH): A life-threatening hypermetabolic state of skeletal muscle triggered by certain anaesthetics in genetically predisposed individuals.

Malignant hyperthermia susceptibility (MHS): The inherited predisposition, often autosomal dominant, to develop MH in response to pharmacological triggers.

Ryanodine receptor type 1 (RyR1): The principal calcium-release channel on the skeletal muscle sarcoplasmic reticulum, central to excitation–contraction coupling and MH pathogenesis.

CACNA1S: The gene encoding the α1 subunit of the dihydropyridine receptor (CaV1.1), which mechanically couples to RyR1 and can harbour rare MH-associated variants.

Dantrolene: The only approved RyR1 antagonist used to counteract MH crisis by inhibiting pathological calcium release.

References

1. Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms. International Journal of Molecular Sciences (2023).
2. Putative malignant hyperthermia mutation CaV1.1-R174W is insufficient to trigger a fulminant response to halothane or confer heat stress intolerance. Journal of Biological Chemistry (2023).
3. The role of CACNA1Sin predisposition to malignant hyperthermia. BMC Medical Genomics (2009).
4. Malignant hyperthermia: a review. Orphanet Journal of Rare Diseases (2015).
5. A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke. Nature Communications (2021).