Determination of a positive malignant hyperthermia (MH) disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation

Molecular genetic methods are used with caution for determining positive ma lignant hyperthermia (MH) disposition in clinical MH diagnosis because of t he genetic variability of this disease. But under defined conditions, genot yping can have an advantage over the standardized in vitro contracture test (IVCT) in respect of invasive approach, specificity, patient compliance, a nd the work and expense involved in the method. We aim to demonstrate this using 10 families with the Arg614Cys mutation in the ryanodine receptor as an example. Fifty-one index patients who had been classified as MH-suscepti ble (MHS) in the IVCT (European MH protocol) after a clinical MH incident o r suspected MH were screened for the Arg614Cys (C1840 --> T) mutation in th e RYR1 gene because this mutation is more common in German MH families (9%) . The family members or those index patients, in whom a Arg614Cys mutation was detectable, were also screened for the presence of this mutation (n = 1 36), and the results were subjected to a more detailed analysis including e xisting IVCT findings (n = 71). The Arg614Cys mutation was identified in a total of 64 members of the 10 in dependent families. In 35 individuals in this group, there was a definite c oncordance between the MHS diagnosis in. the IVCT and the presence of the A rg614Cys mutation. No individual phenotyped as MH-negative carried the muta tion. On the basis of the guidelines of the EMHG for molecular genetic dete ction of MH susceptibility, 29 individuals who bore the Arg614Cys mutation were classified as MHS without the IVCT. If a causal mutation is detected in an MH family, the MHS diagnosis can be deduced without the invasive IVCT in all other mutation carriers. Despite i nclusion of only one (Arg614Cys) of all known MH mutations, the study empha sizes the practical use of a genetic approach for determination of a positi ve MH diagnosis.