Henry Rosenberg

Identification of the Arg1086His mutation in the alpha subunit of the voltage‐dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia

Individuals from a large North American population were screened for the presence of the mutation in the α1 subunit of the voltage‐dependent calcium channel (CACNA1S) that has recently been associated with malignant hyperthermia (MH). This Arg1086His mutation was screened for in 154 MH normal (MHN) individuals and 112 MH susceptible (MHS) individuals, who were diagnosed by the North American protocol of the in vitro contracture test. PCR and restriction enzyme analysis was used to test for the mutation. The Arg1086His mutation in the CACNA1S was not found in any of the MHN individuals. In contrast, two related individuals (grandfather and grandson, father and son of the MH proband) among the MHS group exhibited this mutation. However, a third MHS individual in the same family (granddaughter, cousin of the grandson) did not exhibit this mutation. These results indicate that this mutation may be associated with MH in this family. Genetic alterations in the CACNA1S associated with MH are present in approximately 1% of this North American MHS population.

Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene.

Background:Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type I ryanodine receptor 1 is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods:The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results:Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions:The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.

Identification and functional characterization of a novel ryanodine receptor mutation causing malignant hyperthermia in North American and South American families.

Malignant hyperthermia is a pharmacogenetic disorder associated with mutations in Ca(2+) regulatory proteins. It manifests as a hypermetabolic crisis triggered by commonly used anesthetics. Malignant hyperthermia susceptibility is a dominantly inherited predisposition to malignant hyperthermia that can be diagnosed by using caffeine/halothane contracture tests. In a multigenerational North American family with a severe form of malignant hyperthermia that has caused four deaths, a novel RYR1 A2350T missense mutation was identified in all individuals testing positive for malignant hyperthermia susceptibility. The same A2350T mutation was identified in an Argentinean family with two known fatal MH reactions. Functional analysis in HEK-293 cells revealed an altered Ca(2+) dependence and increased caffeine sensitivity of the expressed mutant protein thus confirming the pathogenic potential of the RYR1 A2350T mutation.

Failure to identify the ryanodine receptor G1021A mutation in a large north American population with malignant hyperthermia

Anesthesia‐induced malignant hyperthermia (MH) is a rare inherited disorder of skeletal muscle. Several mutations in the ryanodine receptor (RYR1) have been found to be causative of MH. The G1021A mutation in the RYR1 is one of the most frequently occurring mutations in European populations. MH normal (165) and MH susceptible (114) North American patients were screened for the presence of the G1021A mutation. This mutation was not found in any of the patients tested. These studies support the absence of this mutation in the normal population. Furthermore, these findings emphasize the importance of viewing the distribution of MH mutations as variable gene pools with frequencies dependent on the geographical location of the population examined.