Nonanesthetic malignant hyperthermia.

S USCEPTIBILITY to malignant hyperthermia (MH) is viewed as a pharmacogenetic trait dependent on exposure to inhalational anesthetics. Outside of the operating room, individuals susceptible to MH are usually asymptomatic. Events that occurred in the absence of anesthetics have been reported over the years and were originally termed awake episodes. In this issue of ANESTHESIOLOGY, two cases of nonanesthetic MH-like episodes triggered by either exposure to environmental heat or infection are described. These two cases raise the question of how at risk the MH susceptible individuals actually are. Classic MH is caused by uncontrolled intracellular Ca release from the sarcoplasmic reticulum mediated by an overactive Ca release channel, the ryanodine receptor 1 (RyR1) (fig. 1). A fulminant anesthetic crisis manifests with tachyarrhythmia and sweating initially, hypercapnia, tachypnea, metabolic acidosis, and rapidly increasing temperature followed by muscle rigidity and rhabdomyolysis. Complications include cardiac arrest, heat stroke, and renal failure. Prompt infusion of dantrolene to block RyR1 is mandatory therapy. MH susceptibility is inherited in an autosomal dominant fashion in man and horse whereas in swine, it is recessive (table 1). In swine, the disorder is even named for these events, porcine stress syndrome, and the trait has been selectively bred because already heterozygous animals have muscle hypertrophy and therefore more meat. Homozygous pigs develop MH triggered by emotional and physical exertion during long-lasting transport in hot, close confinement. The animals either die spontaneously or their meat shows a very obvious, changed characteristic after slaughter that leads to the detection of the disorder. Mating, fighting, heat exposure, and infection trigger episodes that may not display all elements and show delayed or abortive progression. In the very muscular affected quarter horses, nonanesthetic events are frequent in the form of recurrent rhabdomyolysis without evident hyperthermia, spontaneous colic-like episodes, or heat-induced full MH events. In one mare with an especially severe phenotype, a concomitant polysaccharide storage myopathy was identified histologically postmortem. The two unrelated children reported in this article, a boy and a girl, both showed marked hypertrophy and fever-induced MH-like events or recurrent cramping with rigid gait. The boy also had bilateral ptosis and muscle hypotonia indicative of a congenital myopathy, which may have aggravated the phenotype as in the quarter horse. Although both children harbored the same RyR1 variant, p.R3983C, on one allele, the girl had a second mutation, p.D4505H, on the other allele, possibly suggesting an additive effect comparable with the recessive situation in porcine stress syndrome. The notion of an additive effect of RyR1 mutations with other muscle-damaging traits could be supported by a recent report of a fatal heat-induced MH event with heat stroke in a 2-yrold child harboring two RyR1 mutations, p.R4645Q and p.L4320_R4322dup. Furthermore, a recessive RyR1 myopathy has been described recently that displays symmetrical ptosis and muscle hypotonia. However, in MH-susceptible Japanese patients, 10% have compound heterozygous RyR1