Malignant hyperthermia is a rare pharmacogenetic reaction triggered by volatile anaesthetics and/or the depolarising muscle relaxant succinylcholine in susceptible individuals. In 60-75% of the cases, malignant hyperthermia susceptibility is associated with gain-of-function variants in the RYR1 gene. RYR1 encodes for the ryanodine receptor-1, a calcium releasing channel on the sarcoplasmic reticulum in skeletal muscle cells. Gain-of-function RYR1 variants result in altered skeletal muscle ryanodine receptors which are more sensitive to activation. Variants in RYR1 may also give rise to a wide variety of congenital myopathies including central core disease, multi-minicore disease, centronuclear myopathy, King-Denborough syndrome and congenital fibre disproportion. These RYR1-related congenital myopathies and the episodic RYR1-related phenotypes malignant hyperthermia and exertional rhabdomyolysis, have conventionally been considered separate entities. However, recent studies have demonstrated a clinical and histopathological continuum between individuals with RYR1-related congenital myopathies and the episodic RYR1-related phenotypes malignant hyperthermia and exertional rhabdomyolysis.
The aim of this thesis is I) to delineate the clinical spectrum of RYR1-related malignant hyperthermia and/or exertional rhabdomyolysis to improve personalised care, and II) to study the effect of specific RYR1 variants on intracellular calcium release in order to facilitate malignant hyperthermia susceptibility diagnostics by genotyping in carriers of these variants.