Clinical genetics
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Lung disease is the direct cause of death in more than 90% of cystic fibrosis (CF) patients. Proteinase-antiproteinase imbalances are common in CF and alpha-1-antitrypsin (AAT) deficiency. We investigated the hypothesis that the AAT deficiency alleles PiS and PiZ contribute to pulmonary prognosis in CF. ⋯ The remaining six patients showing a PiMS or PiMZ phenotype showed a later onset of chronic Pae lung infection. Our results indicate that PiMS and PiMZ are not associated with worse pulmonary prognosis in CF. These data need to be confirmed in studies with a much larger number of cases.
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Malignant hyperthermia (MH) is an autosomal-dominant disorder of skeletal muscle, triggered by volatile anaesthetics and depolarizing muscle relaxants. The causative defect lies in the control of Ca(2+) release from the sarcoplasmic reticulum in skeletal muscle. Numerous mutations have been detected in the ryanodine receptor 1 (RyR1) gene, but so far an MH-causative role has only been confirmed for 16 human RyR1 mutations. ⋯ The intracellular calcium concentration in response to 4-chloro-m-cresol and to caffeine was investigated by fluorescence calcium imaging. In myotubes the half-maximal activation concentration (EC(50)) for 4-chloro-m-cresol was reduced from 203 micro m (wild type) to 98 micro m (Thr2206Met), and for caffeine from 3.8 mm to 1.8 mm. From the reduction of EC(50) we conclude that the RyR1 Thr2206Met mutation is pathogenic for MH.
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Malignant hyperthermia (MH) is an autosomal dominant disorder that predisposes susceptible individuals to a potentially life-threatening crisis when exposed to commonly used anesthetics. Mutations in the skeletal muscle calcium release channel, ryanodine receptor (RYR1) are associated with MH in over 50% of affected families. ⋯ Subsequent sequencing of RYR1 mutational hot spots revealed a nucleotide substitution of C to T at position 7062, causing a novel amino acid change from Arg2355 to Cys associated with MH in the family. Haplotype analysis of the RYR1 gene area at 19q13 in the family with multiple MH members is an important tool in identification of genetic cause underlying this disease.
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Molecular genetic methods are used with caution for determining positive malignant hyperthermia (MH) disposition in clinical MH diagnosis because of the genetic variability of this disease. But under defined conditions, genotyping can have an advantage over the standardized in vitro contracture test (IVCT) in respect of invasive approach, specificity, patient compliance, and 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. ⋯ On the basis of the guidelines of the EMHG for molecular genetic detection 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 inclusion of only one (Arg614Cys) of all known MH mutations, the study emphasizes the practical use of a genetic approach for determination of a positive MH diagnosis.