A Double Mutation of the Ryanodine Receptor Type 1 Gene in a Malignant Hyperthermia Family with Multiminicore Myopathy

Background and PurposeᄏAt least 100 Ryanodine receptor type 1 (RYR1) mutations associated with malignant hyperthermia (MH) and central core disease (CCD) have been identified, but 2 RYR1 mutations accompanying multiminicore myopathy in an MH and/or CCD family have been reported only rarely. MethodsᄏFifty-three members of a large MH family were investigated with clinical, histopathologic, RYR1 mutation, and haplotyping studies. Blood creatine kinase (CK) and myoglobin levels were also measured where possible. ResultsᄏSequencing of the entire RYR1 coding region identified a double RYR1 mutation (R2435H and A4295V) in MH/CCD regions 2 and 3. Haplotyping analysis revealed that the two missense heterozygous mutations (c.7304G>A and c.12891C>T) were always present on a common haplotype allele, and were closely cosegregated with histological multiminicores and elevated serum CK. All the subjects with the double mutation showed elevated serum CK and myoglobin, and the obtained muscle biopsy samples showed multiminicore lesions, but only two family members presented a late-onset, slowly progressive myopathy. ConclusionsᄏWe found multiminicore myopathy with clinical and histological variability in a large MH family with an unusual double RYR1 mutation, including a typical CCD-causing known mutant. These results suggest that multiminicore lesions are associated with the presence of more than two mutations in the RYR1 gene.ope

Malignant hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000–100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%

Flexibilitaet - ein Konzept fuer die Studienreform?

IAB-93-1300-11 AS 209 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Implementationsprobleme beschaeftigungsorientierter Flexibilitaetskonzepte in der Studienreform

SIGLEAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel A 159769 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Challenges in the diagnosis and management of severe Pneumocystis jirovecii pneumonia in a non-HIV-infected patient - A case report

A 64-year-old woman was referred to our hospital due to progressive dypnoea for the past week, combined with fever and type 1 respiratory failure. White blood cell count and procalcitonin level were normal. The Chest X-ray showed bilateral disseminated pulmonary infiltrates. Within the next 24 hours the patient developed a severe ARDS. A first diagnostic work-up for typical and atypical pathogens as well as serological tests for CMV, RSV, HIV and HSV were negative. Analysis of a second bronchoalveolar lavage fluid revealed Pneumocystis jiroveci DNA. The patient was successfully treated with trimethoprim-sulfamethoxazole and off label use with caspofungin. The cause of the infection was a six week treatment with dexamethasone. The patient developed a toxic epidermal necrolysis during further course, but completely recovered. Pneumonia with Pneumocystis jirovecii must also be taken into account in non-HIV patients, whenever there are any indications that cellular immunity may be depressed