Malignant Hyperthermia: A Review of Clinical Phenotype and Molecular Genotype

Malignant hyperthermia (MH) is a rare inherited skeletal muscle disorder related to general anaesthesia. It is primarily caused by a mutation in the RYR1 gene. The RYR1 gene codes for the ryanodine receptor 1, which is responsible for calcium release in skeletal muscle. An episode of malignant hyperthermia is typically triggered by volatile anaesthetic agents such as halothane, isoflurane, desflurane, etc, depolarising skeletal muscle relaxants such as succinylcholine, and caffeine which cause contractures in skeletal muscles. These contractures are enhanced when calcium reuptake is inhibited in the sarcoplasmic reticulum. Exposure to a triggering agent causes a substantial increase of intracellular calcium, which results in a massive, life threatening, hypermetabolic response.

There are presently over 40 known mutations in the RYR1 gene, which is on the long arm of chromosome 19. Most of these mutations are found on three major regions, malignant hyperthermia/central core disease susceptibility regions I, II, and III. Additionally, the CACNA1S gene mutation plays a similar role in malignant hyperthermia. This gene is found on the long q arm of chromosome 1 and most of these mutations are found at position 32.1.

The likelihood that a patient will develop malignant hyperthermia on exposure to a triggering agent is determined on a universal points system, ranging from 0 (not likely to develop MH) to 6 (almost certain to develop MH). Severity is determined by a recognised clinical grading system, the Delphi method, which incorporates clinical findings/manifestations, and uses a points system, where a higher score denotes a more severe clinical manifestation.