Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility.
BACKGROUND
Malignant hyperthermia susceptibility (MHS), an uncommon syndrome often inherited as an autosomal dominant trait, is characterized by a genetic and clinical heterogeneity. In this article, the authors described six pedigrees in which both parents of MHS patients were diagnosed with MHS by an diagnostic test. Haplotype and mutation analysis revealed that more than one MHS genetic trait was present in these families.


METHODS
A panel of 104 MHS families were investigated with a caffeine halothane contracture test on muscle biopsy specimens. When possible, blood creatine kinase concentrations of MHS patients were measured. Haplotyping studies were conducted with chromosome 19q13.2 polymorphic markers and mutations were searched for in patients' DNA.


RESULTS
In six families, the diagnostic test and genetic studies demonstrated that both, apparently unrelated, parents of MHS patients were MHS. In three families, homozygous or compound heterozygous individuals for RYR1 mutations were characterized at a molecular level. In one family, a compound heterozygous patient harboring a RYR1 mutation and a CACNA1S mutation was identified. While patients with two mutated alleles did not show differences in their muscle response to halothane or caffeine, their creatinine kinase concentrations were significantly elevated compared with the heterozygous patients.


CONCLUSIONS
Based on genetic and diagnostic test data, more than one MHS allele associated with the MHS phenotype was evidenced in four families. These data should be considered in view of the use of genetics for the diagnosis of MHS and when reaching conclusions of genetic heterogeneity in MHS families. Taking into account the usual dominant mode of transmission of MHS and the size of the investigated population, the authors propose an evaluation of the incidence of the MHS in the general population based on genetic data.
Monnier
Nicole
N
Department of Anesthesiology, University Hospital, Grenoble, France.
Krivosic-Horber
Renée
R
Payen
Jean-François
JF
Kozak-Ribbens
Geneviève
G
Nivoche
Yves
Y
Adnet
Pascal
P
Reyford
Hugo
H
Lunardi
Joël
J
D000293:Adolescent; D000328:Adult; D020746:Calcium Channels, L-Type / Q000235:genetics*; D003402:Creatine Kinase / Q000097:blood; D020022:Genetic Predisposition to Disease; D006801:Humans; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D003402:Creatine Kinase