Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a 17-year-old boy with Becker muscular dystrophy (BMD) who developed hyperthermia and heart failure after general anesthesia. He presented clinical features of malignant hyperthermia (MH), and had masseter spasm and elevated body temperature (38.7 degrees C) with very high serum CK activity (107,000 IUl-1). Dystrophin tests confirmed a clinical diagnosis of BMD in the patient, i.e. faint and patchy immunostaining pattern of skeletal muscle, truncated dystrophin protein and a deletion of exons 3 and 4 of the dystrophin gene. To inquire into the mechanism of MH associated in the patient, we tested caffeine contracture reaction by the skinned fiber method. We found an increased sensitivity to caffeine only in type 1 muscle fibers. The rate of Ca(2+)-induced Ca2+ release (CICR) was normal, suggesting that the mechanism of "MH" observed in our patient with BMD is not the same as that of classical MH. A possible mechanism might be related to derangements of the sarcoplasmic reticulum membrane in BMD, which sensitize the membrane to caffeine or other agents.
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PMID:Malignant hyperthermia in a patient with Becker muscular dystrophy: dystrophin analysis and caffeine contracture study. 771 42

Duchenne muscular dystrophy (DMD) causes profound and progressive muscle weakness and loss, resulting in early death. DMD is usually caused by frameshifting deletions in the gene DMD, which leads to absence of dystrophin protein. Dystrophin binds to F-actin and components of the dystrophin-associated glycoprotein complex and protects the sarcolemma from contraction-induced injury. Antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach aimed at restoring the DMD reading frame and allowing expression of an intact dystrophin glycoprotein complex. To date, low levels of dystrophin protein have been produced in humans by this method. We performed a small-molecule screen to identify existing drugs that enhance antisense-directed exon skipping. We found that dantrolene, currently used to treat malignant hyperthermia, potentiates antisense oligomer-guided exon skipping to increase exon skipping to restore the mRNA reading frame, the sarcolemmal dystrophin protein, and the dystrophin glycoprotein complex in skeletal muscles of mdx mice when delivered intramuscularly or intravenously. Further, dantrolene synergized with multiple weekly injections of antisense to increase muscle strength and reduce serum creatine kinase in mdx mice. Dantrolene similarly promoted antisense-mediated exon skipping in reprogrammed myotubes from DMD patients. Ryanodine and Rycal S107, which, like dantrolene, targets the ryanodine receptor, also promoted antisense-driven exon skipping, implicating the ryanodine receptor as the critical molecular target.
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PMID:Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy. 2324 44