Molecular Genetic Analysis of Malignant Hyperthermia

Abstract

Malignant hyperthermia (MH) is the most common cause of unexpected death due to general anaesthesia using common volatile anaesthetic agents. It is an autosomal dominant pharmacogenetic abnormality of skeletal muscle with a high degree of genetic and clinical variability. It is associated with elevated calcium ion levels in skeletal muscle cells. Apparently it is caused by defect in a calcium release channel, encoded by theRYRJ gene which is located on chromosome 19q. Studies show only around 50% of MH families are linked to the RYR1 gene so that heterogeneity for this abnormality is suggested. Further studies proved more genes or a candidate regions such as chromosome 7q, 3q are involved in malignant hyperthermia susceptibility. In this search for more understanding of the malignant hyperthermia disorder and for identifying the gene or genes which may be causative in MH, some UK MH families for the RYR1 gene and other candidate regions were studied. Furthermore based on reports of the correlation between MH and mutations in the RYR1 gene in 19-linked families the screening of UK MH families for three mutations from eight putative causative mutations in the RYR] gene was carried out. The ultimate goal of this MH project has been to identify individuals susceptible to MH in advance of anaesthesia. Genetic analysis by direct mutation testing or linkage analysis potentially offers an alternative non-invasive and accurate test for diagnosis of MH susceptibility. However once the linkage relationships are firmly established, they provide a sensitive, non-invasive technique for the presymptomatic diagnosis of MH.