TY  - JOUR
A1  - Klingler, Werner
A1  - Heiderich, Sebastian
A1  - Girard, Thierry
A1  - Gravino, Elvira
A1  - Heffron, James J. A.
A1  - Johannsen, Stephan
A1  - Jurkat-Rott, Karin
A1  - Rüffert, Henrik
A1  - Schuster, Frank
A1  - Snoeck, Marc
A1  - Sorrentino, Vincenzo
A1  - Tegazzin, Vincenzo
A1  - Lehmann-Horn, Frank
T1  - Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study
JF  - Orphanet Journal of Rare Diseases
N2  - Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. 
Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. 
Results: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. 
Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.
KW  - susceptibility
KW  - central core disease
KW  - skeletal muscle
KW  - North American
KW  - malignant hyperthermia
KW  - succinylcholine
KW  - suxamethonium
KW  - volatile anesthetics
KW  - RyR1 mutations
KW  - New Zealand
KW  - inhalation anesthetics
KW  - sarcoplasmic reticulum
KW  - ryanodine receptor gene
KW  - vitro contracture test
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117630
SN  - 1750-1172
VL  - 9
IS  - 8
ER  - 
TY  - JOUR
A1  - Mitchell, Anna L.
A1  - Macarthur, Katie D. R.
A1  - Gan, Earn H.
A1  - Baggott, Lucy E.
A1  - Wolff, Anette S. B.
A1  - Skinningsrud, Beate
A1  - Platt, Hazel
A1  - Short, Andrea
A1  - Lobell, Anna
A1  - Kampe, Olle
A1  - Bensing, Sophie
A1  - Betterle, Corrado
A1  - Kasperlik-Zaluska, Anna
A1  - Zurawek, Magdalena
A1  - Fichna, Marta
A1  - Kockum, Ingrid
A1  - Eriksson, Gabriel Nordling
A1  - Ekwall, Olov
A1  - Wahlberg, Jeanette
A1  - Dahlqvist, Per
A1  - Hulting, Anna-Lena
A1  - Penna-Martinez, Marissa
A1  - Meyer, Gesine
A1  - Kahles, Heinrich
A1  - Badenhoop, Klaus
A1  - Hahner, Stephanie
A1  - Quinkler, Marcus
A1  - Falorni, Alberto
A1  - Phipps-Green, Amanda
A1  - Merriman, Tony R.
A1  - Ollier, William
A1  - Cordell, Heather J.
A1  - Undlien, Dag
A1  - Czarnocka, Barbara
A1  - Husebye, Eystein
A1  - Pearce, Simon H. S.
T1  - Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts
JF  - PLOS ONE
N2  - Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. 
Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. 
Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. 
Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. 
Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
KW  - Graves disease
KW  - identical twins
KW  - hashimotos-thyroiditis
KW  - population
KW  - gene
KW  - polymorphism
KW  - susceptibility
KW  - prevalence
KW  - haplotype
KW  - rheumatoid arthritis
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117105
VL  - 9
IS  - 3
ER  -