Advances in DNA technology have supported the concept for a central role of the ryanodine receptor gene RYR1 in the pathophysiology of malignant hyperthermia. The identification of a series of markers around the region of RYR1 has enabled a detailed genetic analysis to be performed for families susceptible to malignant hyperthermia. Initially it was hoped that genetic studies would supersede the in vitro contracture test used to diagnose malignant hyperthermia and provide insight into the actual underlying defect. However, only 50 per cent of all malignant-hyperthermia-susceptible families studied worldwide segregated with RYR1, and furthermore RYR1 linkage could be firmly excluded in some families. Genetic heterogeneity has been described in both European and North American families. Searches have been performed in other potential candidate areas of the genome, in particular the regions for the protein subunits of the dihydropyridine receptor.
Eight different mutations in RYR1 have been identified, and approximately 20 per cent of families definitely linked to RYR1 have a mutation. Furthermore, the mutation does not always segregate with the in vitro contracture test result within a family. For example, an individual may be 'genetically' susceptible to malignant hyperthermia but malignant hyperthermia negative by the in vitro contracture test, or vice versa. The genetics of malignant hyperthermia is quite complex, and further elucidation is needed before DNA studies on malignant hyperthermia families can be considered as a possible alternative to the in vitro contracture test as a screening test (Hopkins i et, §1 1994).
Although malignant hyperthermia is rarely associated with central core disease either clinically or histologically, central core disease is commonly but not invariably associated with malignant hyperthermia (Halsajl etal 1996). Central core disease has been shown to be linked to RYR1 and several RYR1 mutations have been described in families with this disease.
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