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Segregation of malignant hyperthermia, central core disease and chromosome 19 markers
J L Curran1, W J Hall, P J Halsall
1Malignant Hyperthermia Investigation Unit, University of Leeds, St James's University Hospital, UK.
Abstract:
Malignant hyperthermia (MH) is an autosomal dominant disorder presenting under general anaesthesia. It is occasionally associated with a myopathy, central core disease (CCD), named after its predominant histochemical characteristic. The penetration of CCD is variable, but typically affected individuals show delayed motor milestones in infancy and remain physically compromised. It was thought until recently that individuals with CCD were always susceptible to MH. Individuals from eight CCD families were screened for the presence of 13 mutations in the skeletal muscle ryanodine receptor gene, reported previously to be associated with MH and/or CCD: none was detected. In seven of these families, where CCD and MH co-existed, we examined the segregation of CCD, MH susceptibility and chromosome 19q markers. In four families, 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 segregation between MH and these markers. This is unequivocal evidence that CCD, in common with MH, is genetically heterogeneous. In the two other families, CCD segregated with chromosome 19 markers but not all individuals with CCD were susceptible to MH. We recommend determination of MH susceptibility in all patients with CCD, irrespective of the MH status of their relatives with CCD.
Insights
Malignant hyperthermia (MH) and central core disease (CCD) are genetically distinct conditions. This study reveals genetic heterogeneity in CCD, showing it does not always correlate with MH susceptibility.
Area of Science:
- Genetics
- Neuromuscular Disorders
- Anesthesiology
Background:
- Malignant hyperthermia (MH) is a severe pharmacogenetic disorder triggered by anesthetics.
- Central core disease (CCD) is a congenital myopathy often associated with MH susceptibility.
- Previous assumptions linked CCD and MH susceptibility directly.
Purpose of the Study:
- To investigate the genetic relationship between CCD and MH susceptibility.
- To determine if CCD always implies MH susceptibility.
- To explore the genetic heterogeneity of CCD.
Main Methods:
- Screening of eight CCD families for 13 known RYR1 gene mutations associated with MH/CCD.
- Segregation analysis of CCD, MH susceptibility, and chromosome 19q markers in affected families.
- Examination of co-segregation patterns within pedigrees.
Main Results:
- No known MH/CCD mutations were detected in individuals from eight CCD families.
- Complete co-segregation of CCD, MH susceptibility, and chromosome 19 markers was observed in four families.
- Lack of co-segregation between CCD, MH, and chromosome 19 markers was found in one large pedigree, indicating genetic heterogeneity.
- In two families, CCD segregated with chromosome 19 markers, but MH susceptibility varied among affected individuals.
Conclusions:
- Central core disease (CCD) exhibits genetic heterogeneity and is not always linked to malignant hyperthermia (MH) susceptibility.
- MH susceptibility should be determined for all patients with CCD, regardless of family history.
- This research clarifies the complex genetic relationship between CCD and MH.