Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study

Area of Science:

• Anesthesiology
• Pharmacogenetics
• Molecular Biology

Background:

• Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder triggered by anesthetics.
• It involves excessive calcium (Ca2+) release from skeletal muscle, primarily due to mutated ryanodine receptor type 1 (RyR1).
• Understanding MH triggers and mechanisms is crucial for patient safety.

Purpose of the Study:

• To analyze clinical MH events, muscle contracture data, genetic factors, and pharmacological triggers.
• To identify factors contributing to variable MH presentation and complex pathomechanisms.

Main Methods:

• Multi-center study of patients with confirmed MH susceptibility (MHS) or equivocal (MHE) in vitro contracture tests (IVCT).
• Evaluation of crises using a clinical grading scale (CGS), IVCT results, and genetic screening.
• In vitro studies on Ca2+ release from sarcoplasmic reticulum (SR) by succinylcholine (SCh) and volatile anesthetics.

Main Results:

• 81% of MH crises resulted from combined volatile anesthetics and SCh; 18% from volatile anesthetics alone.
• Male gender and younger age (<12 years) were prevalent. CGS correlated with IVCT results.
• 103 of 200 patients had RyR1 variants (14 novel); mutation location affected CGS. SCh did not directly cause Ca2+ release in rat SR vesicles.

Conclusions:

• MH risk is influenced by patient factors (male gender, young age, RyR1 mutations) and drugs lowering myoplasmic Ca2+ release threshold.
• SCh may accelerate MH by promoting Ca2+ influx and indirect RyR1 activation.
• Combined SCh and volatile anesthetic administration is the most common cause of MH crises.