The Genetics of Malignant Hyperthermia and Related Muscular Syndromes

Abstract

To the Editor: The review by Capacchione and Muldoon1 discusses relationships between malignant hyperthermia (MH) and other muscular diseases presenting with some of the clinical features of MH. The task is made more difficult because of the uncertain relationships between a positive in vitro contracture test for halothane and caffeine, specific expression of the triggering mechanism of MH, and the presence of a genetic defect in the muscular ryanodine receptor type 1 (RYR1) gene. Capacchione and Muldoon state that “a negative RYR1 screen with a positive contracture test does not necessarily mean that the patient is not MH susceptible as there are likely yet unidentified non-RYR1 mutations that confer MHS (MH susceptibility).” Indeed, in the 20% to 30% of individuals lacking an RYR1 mutation, genetic alterations of other proteins involved in calcium release or its regulation could be present.2 Monnier et al.3 described such a mutation in the α-1 subunit of the human dihydropyridine receptor responsible for MH in a French family. Protasi et al.2 and Dainese et al.,4 studying knockout mice lacking skeletal muscle calsequestrin, a calcium-binding and buffering protein involved in the modulation of calcium release from RYR1, suggested that this mutation could be involved in MH and environmental heat stroke. On the basis of analogies between MH and catecholaminergic polymorphic ventricular tachycardia, a cardiac disorder caused by mutation in the cardiac RYR2 gene, MacLennan and Chen5 suggested that both diseases may have a common mechanism. In fact, a mutation in RyR can decrease the threshold for calcium release from sarcoplasmic reticulum, and a mutation in calsequestrin can increase the free calcium concentration over the same threshold, giving rise, in the presence of halothane and catecholamines, to contracture (MH) or arrhythmias (catecholaminergic polymorphic ventricular tachycardia), respectively. It is also possible that a mutation in different genes involved in the production and regulation of different calcium handling proteins could explain not only MH and similar muscular diseases but also some cardiac-related diseases sharing the same genetic anomaly. Luca Siracusano, MD Viviana Girasole, MD Department of Neuroscience, Psychiatric and Anesthesiological Sciences University of Messina Messina, Italy [email protected] or [email protected]