A reliable test for susceptibility to Malignant Hyperthermia (MH) was developed in 1970 by Drs Kalow and Britt at the University of Toronto, modified a year later by Dr Richard Ellis, when he performed the test at 37oC.
The test involved exposing a fascicle of quadriceps muscle to halothane and caffeine (a number of chemicals were used before choosing these), and assessing contracture status of the muscle.
Ryanodine (a plant alkaloid that causes reversible contracture of muscle) and later chlorocresol were adjuncts to testing but are not included at present as part of the standard protocol.
This test remains the 'gold standard' for testing for susceptibility to MH. The test parameters are set to minimise (potentially eliminate) false negative test results but this is at the expense of a small percentage of false positive results. Further family testing may help to identify false positive results.
This test has been performed at Palmerston North Hospital since 1986 (and at Massey University for 6 years previously) and has been very useful in identifying patients susceptible to MH.
The muscle biopsy test is invasive (i.e. it involves a procedure that penetrates the body) and the site of the muscle can be uncomfortable for a week or two. Extensive research has been undertaken to find a minimally invasive test.
Biochemical tests, tests relating to the components of blood and physical tests have been used, but the specificity and sometimes the sensitivity have been unacceptable.
In 1989 Dr Tommy McCarthy described a DNA test, or gene test, that was hoped would identify patients susceptible to MH. Calcium is an essential component of muscle function, and the test he described identified an abnormality in the gene encoding the formation of the calcium release channel.
This abnormality resulted from a mutation in the gene (i.e. one of the thousands of building blocks or nucleotides in the gene is replaced by another, affecting the 'instructions' the gene transmits for the building of the calcium channel). This single point mutation results in the abnormality in the calcium release channel causing increased release of calcium into the interior of the cell, resulting in malignant hyperthermia.
It was hoped that one mutation would be responsible for all cases of MH. This has not happened. Over 30 mutations have been described affecting <50% of all known susceptible families.
Ten mutations have been identified in 15 New Zealand families. Identification of a "causative" mutation, i.e. abnormal calcium release has been demonstrated in an appropriate assay, indicates MH susceptibility. A negative or normal DNA test in a family with a 'causative mutation' does not exclude MH susceptibility. It is possible that more than one mutation exists in some families. Until all possible mutations co-segregating with MH are identified, negative DNA tests need to be confirmed by a muscle biopsy.
Mr Matthew Batlajeri
Mrs Sharon Heslop
Mr Shawn McFlinn