The anesthetic myopathies and malignant hyperthermias.

Fatal destruction of skeletal muscle coincident with exposure to specific drugs used during anethesia has been recognized as a potentially heritable disorder for more than 30 years. Variable expressivity and incomplete penetrance of the clinical malignant hyperthermia phenotype, together with inherent drawbacks of the in-vitro contracture test confounded efforts to discover the underlying pathogenesis until the application of molecular genetic techniques. On the basis of linkage analysis and mapping of positional candidate genes, mutant alleles at loci on chromosomes 1q, (dihydropyridine-sensitive L-type calcium channel-A1S); 3q, 5p, 7q (dihydropyridine-sensitive L-type calcium channel-LA2), and 19q (ryanodine receptor) are now believed to account for up to 50% of human malignant hyperthermia susceptibility. Although inconsistent genotype-phenotype correlations and doubts regarding the causality of each mutant allele persist, the definition of malignant hyperthermia and relevance of molecular genetic data to the problems of family counseling, population screening, and improved resolution of the malignant hyperthermia phenotype must now be appraised in view of significant locus and allelic genetic heterogeneity.