MALIGNANT HYPERTHERMIA: BIOCHEMICAL ASPECTS OF THE ACUTE EPISODE

Early studies indicated that the pharmacogenetic disorder, malignant hyperthermia (MH), was inherited as an autosomally dominant trait in humans [3]. More recent interpretations indicate that MH may be inherited through more than a single gene [9, 10] and that the pattern of inheritance may vary from recessive to dominant. This uncertainty about the mode of inheritance of human MH has contributed to the confusion which abounds in biochemical studies of the molecular aetiology of the syndrome. It now seems unlikely that MH is caused by a single enzyme or protein lesion such as is seen, for instance, in McArdle's disease or phenylketonuria. While the nature of the genetic abnormality remains unclear, there is good evidence that the fundamental defect is located in the fibres of the skeletal musculature. For example: tubocurarine will not block induc-tion of MH by halothane; muscular rigidity is one of the first signs of onset of an MH episode; the neuromuscular blocker dantrolene blocks develop-ment of the syndrome and halothane-induced contractures of biopsy strips of muscle from MH susceptible individuals; the resting intracellular free calcium ion concentration of MH muscle fibres is increased; and up to 70 % of subjects show increased muscle-specific serum creatine phosphokinase activity [6, 16, 17]. Indeed, the so-called MH syndrome is now recognized as a metabolic disorder of skeletal muscle in the two major treatises on muscle disease [7, 21]. The clinical signs and symptoms of acute malignant hyperthermia have been described by numerous authors in case reports; briefly, the typical symptoms are rigidity, metabolic and respiratory acidosis, tachycardia, hyperkalaemia, hyperthermia and myoglobinuria. The severit