Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family.

Malignant hyperthermia (MH) is a potentially lethal inherited pharmacogenetic syndrome due to a dysfunction of the intracellular calcium regulation of skeletal muscle following administration of volatile anaesthetics and depolarizing muscle relaxants. The ryanodine receptor of skeletal muscle (RYR1), which is an intracellular calcium release channel, has been proposed to be a candidate structure for the MH defect. In some families with a history of MH a C1840-T nucleotide exchange has been found in the RYR1 gene which cosegregates with the MH susceptible phenotype. Sixteen individuals (5 males and 11 females; age 8-68 years, 7 MH susceptible, 9 MH non-susceptible) of a family with a history of MH were screened for the C1840-T mutation in the RYR1 gene using standard methods. DNA fingerprinting was performed in order to verify the kinship. MH susceptibility was determined using the standard in vitro contracture test with halothane and caffeine. The present article describes a German MH pedigree carrying a spontaneous C1840-T mutation. The mutation was detected in one individual of the third generation. This person was classified as MH susceptible according to the in vitro contracture test protocol. None of the other family members (6 MH susceptible and 9 MH non-susceptible persons), including the parents of the child carrying the mutation, presented the C to T nucleotide exchange at position 1840.This novel observation clearly demonstrates that only the detection of the C1840-T mutation may lead to the diagnosis of MH susceptibility, but missing the mutation does not justify diagnosing a patient as non-susceptible within a single pedigree.