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Pediatric heart failure remains poorly understood, distinct in many aspects from adult heart failure. Limited data point to roles of altered mitochondrial functioning and in particular, changes in mitochondrial lipids, especially cardiolipin. Barth syndrome is a mitochondrial disorder caused by tafazzin mutations that lead to abnormal cardiolipin profiles. Patients are afflicted by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay. A mouse model of Barth syndrome was developed a decade ago, which relies on a doxycycline-inducible shRNA to knock down expression of tafazzin mRNA ("TAZKD"). Our objective was to review published data from the TAZKD mouse to determine its contributions to our pathogenetic understanding of, and potential treatment strategies for, Barth syndrome. In regard to the clinical syndrome, the reported physiological, biochemical, and ultrastructural abnormalities of the mouse model mirror those in Barth patients. Using this model, the PPAR pan-agonist bezafibrate has been suggested as potential therapy because it ameliorated the cardiomyopathy in TAZKD mice, while increasing mitochondrial biogenesis. A clinical trial is now underway to test bezafibrate in Barth syndrome patients. Thus, the TAZKD mouse model of Barth syndrome has led to important insights into disease pathogenesis and therapeutic targets, which can potentially translate to pediatric heart failure.
This article was published in the following journal.
Name: American journal of physiology. Heart and circulatory physiology
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Rare congenital X-linked disorder of lipid metabolism. Barth syndrome is transmitted in an X-linked recessive pattern. The syndrome is characterized by muscular weakness, growth retardation, DILATED CARDIOMYOPATHY, variable NEUTROPENIA, 3-methylglutaconic aciduria (type II) and decreases in mitochondrial CARDIOLIPIN level. Other biochemical and morphological mitochondrial abnormalities also exist.
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