Segregation of malignant hyperthermia, central core disease and chromosome19 markers

Malignant hyperthermia (MH) is an autosomal dominant disorder presenting un der general anaesthesia. It is occasionally associated with a myopathy, cen tral core disease (CCD), named after its predominant histochemical characte ristic. The penetration of CCD is variable, but typically affected individu als show delayed motor milestones in infancy and remain physically compromi sed. It was thought until recently that individuals with CCD were always su sceptible to MH. Individuals from eight CCD families were screened for the presence of 13 mutations in the skeletal muscle ryanodine receptor gene, re ported previously to be associated with MH and/or CCD: none was detected. I n seven of these families, where CCD and MH co-existed, we examined the seg regation of CCD, MH susceptibility and chromosome 19q markers. In four fami lies, there was complete co-segregation between MH, CCD and the chromosome 19 markers, but in one large pedigree there was a clear lack of segregation of CCD with either MH or chromosome 19 markers and there was no segregatio n between MH and these markers. This is unequivocal evidence that CCD, in c ommon with MH, is genetically heterogeneous. In the two other families, CCD segregated with chromosome 19 markers but not all individuals with CCD wer e susceptible to MH. We recommend determination of MH susceptibility in all patients with CCD, irrespective of the MH status of their relatives with C CD.