title: [Homozygous and compound heterozygous RYR1 mutations. New findings on prevalence and penetrance of malignant hyperthermia].
abstract: BACKGROUND
  Malignant hyperthermia (MH) is a life-threatening, acute pharmacogenetic disorder mostly due to heterozygous mutations in the ryanodin receptor 1 (RYR1) gene. Diagnosis is generally confirmed by the in vitro contracture test (IVCT). In this study the genotype-phenotype correlation was analyzed and the presumed prevalence of MH is discussed.
  
  
  METHODS
  After the diagnosis of MH susceptibility by the IVCT DNA samples of 44 patients were analyzed for mutations in the RYR1 gene using the polymerase chain reaction and sequencing. For genotype-phenotype correlation, the mutation analysis data were compared with the IVCT data.
  
  
  RESULTS
  Out of the 44 patients tested 13 were identified with a heterozygous mutation, 1 patient with a homozygous mutation (c.1840C>T) and 1 patient with compound heterozygous mutations (c.1840C>T and c.6487C>T). The two patients with two mutated alleles showed a stronger response in the IVCT compared to those with only one mutated allele. Patients with one RYR1 mutation displayed significantly higher contractures in the IVCT than patients without RYR1 mutations.
  
  
  CONCLUSIONS
  In the two patients described the presence of two mutated RYR1 alleles seemed to have an additive effect on the functional restriction of the (RYR1 receptor and to lead to a stronger response both in the IVCT and with regard to clinical signs. The patients with no detected RYR1 mutations possibly have a RYR1 mutation with smaller effects outside the hot spot regions tested and/or false positive IVCT results. The data from a small patient group indicate a substantially higher prevalence of MH with a correspondingly lower penetrance in the German population than previously assumed.
authors.affiliation: Institut für Humangenetik, Universitätsmedizin der Johannes Gutenberg-Universität, Langenbeckstr. 1, 55131, Mainz, Deutschland.
authors.forename: S
authors.initials: S
authors.lastname: Wolak
authors.forename: B
authors.initials: B
authors.lastname: Rücker
authors.forename: N
authors.initials: N
authors.lastname: Kohlschmidt
authors.forename: S
authors.initials: S
authors.lastname: Doetsch
authors.forename: O
authors.initials: O
authors.lastname: Bartsch
authors.forename: U
authors.initials: U
authors.lastname: Zechner
authors.forename: I
authors.initials: I
authors.lastname: Tzanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002648:Child; D004247:DNA / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000453:epidemiology* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D019683:Penetrance; D015995:Prevalence; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D055815:Young Adult
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA