Diagnosis of malignant hyperthermia: a comparison of the in vitro contracture test with the molecular genetic diagnosis in a large pedigree

• Published in: Journal of medical genetics 1996-01, Vol.33 (1), p.18-24
• Main Authors: Healy, J M, Quane, K A, Keating, K E, Lehane, M, Heffron, J J, McCarthy, T V
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Contracture; Diseases of the osteoarticular system; Female; Genetic Markers - genetics; Humans; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Malignant Hyperthermia - diagnosis; Malignant Hyperthermia - genetics; Medical sciences; Mutation; Pedigree
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.33.1.18

Malignant hyperthermia (MH) is an inherited skeletal muscle disorder and is one of the major causes of death resulting from anaesthesia. MH is currently diagnosed by the in vitro contracture test performed on a muscle biopsy. Genetic linkage analysis on an Irish MH pedigree showed that when the thresholds for the standardised European protocol for MHS diagnosis was applied, linkage between the MHS phenotype and the RYR1 locus was excluded. When we raised the threshold values for assignment of MHS status and assumed MHN diagnosis in subjects where this threshold was not attained, tight linkage between MHS and RYR1 markers was observed, suggesting that MHS is linked to the RYR1 locus in this pedigree. Confirmation of these results was borne out by the fact that all of the MHS patients in the pedigree exceeding the raised threshold carried the known MHS Gly341Arg RYR1 mutation. The results obtained could be explained (1) by false positive diagnosis of MHS in the recombinant subjects, (2) by the presence of a mutation in a predisposing gene other than RYR1, or (3) by the presence of mild subclinical myopathies. The implications of these results for heterogeneity studies is discussed.