British Malignant Hyperthermia Association (BMHA)
The BMHA exists to help
people with
Malignant Hyperthermia
Registered Charity
No 1007739
The BMHA was successful in gaining a Big Lottery Fund Research Grant, to investigate how many UK families could be helped by a DNA test. Approval for the Grant was only the first step in a lengthy process which was required before the work could begin. The Grant eventually started in April 2005 and ended in October 2008.
A final summary of the overall outcome of the research follows but the original yearly progress reports (including some of the background to the need for the research) are available. Previous Lottery Reports- PDF
Was the project a success?
The project helped us to contact the majority of MH families registered with the Leeds MH Unit by combining the Leeds and BMHA patient databases. This enabled us to increase the number of UK families who could benefit from predictive DNA screening from 25% at the start of the project to 41% by the end owing to the collection of fresh blood samples for analysis. This was the main aim of the project.
The project also identified novel RYR1 mutations in some families and previously reported mutations, but as yet of unknown biological significance in others. There is little point in identifying new gene mutations for diagnostic use unless it can be shown that they have a role in causing MH ie a functional (or causative) effect. Only then can they be used to the benefit of families in diagnosis. This rationale is in keeping with guidelines laid out by the European MH Group (www.emhg.org). As a result of the Lottery project, the Leeds MH Unit now has an independent project in place to assess if any of the novel or uncharacterised mutations are likely to have a causative effect. If so this will further increase the number of mutations that can be used for MH diagnosis and thus the number of families who would benefit from DNA testing.
If all the different types of RYR1 mutations are considered together, a total of 60-70% of UK MH patients are now accounted for by changes in the RYR1 gene. At the beginning of the project it was predicted that 90% of UK MH cases were due to changes in the RYR1 gene. The project has highlighted the complexity of the MH condition and that the RYR1 gene plays a more conservative role than initially thought.
By showing that the RYR1 gene plays a less than predicted role, other factors must be playing a part for around 30% of MH families in the UK. During this project we have been able to identify a panel of 29 families in whom both RYR1 and CACNA1S (another gene linked to MH) have been excluded. These families are being entered into other projects to screen for alternative genes and may lead to the discovery of a new MH causing gene.
Thus the aim of the project has been successfully achieved in that there has been a significant increase in the characterisation of MH families in the UK and therefore increased availability of a genetic test for patients. Interestingly, it has also lead to at least 2 other lines of research work for the future.
Many individuals have contributed to the success of this project and we would like to thank all concerned in particular the patients themselves who generously gave their time as well as their blood!
Papers resulting from the Lottery project
1. Carpenter D, Ismail A, Robinson RL, Ringrose C, Booms P, Iles DE, Halsall J, Steele D, Shaw M-A, Hopkins PM, 2009. A RYR1 mutation associated with recessive congenital myopathy and dominant malignant hyperthermia. Muscle and Nerve, in press
2. Robinson RL, Carpenter D, Halsall PJ, Iles DE, Booms P, Steele D, Hopkins PM, Shaw M-A, 2009. Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility. British Journal of Anaesthesia, in press
3. Carpenter D, Ringrose C, Leo V, Morris A, Robinson RL, Halsall PJ, Hopkins PM, Shaw M-A. New variants in the dihydropyridine receptor gene, CACNA1S and predisposition to malignant hyperthermia. Manuscript under review for BMC Medical Genetics
4. Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ, Shaw M-A, Hopkins PM: RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mut 2002; 20:88-97
Presentations relating to these papers have also been presented at CMGS, British Society of Human Genetics and the European MH Group