BARTH SYNDROME: A COMPREHENSIVE REVIEW OF CARDIOLIPIN METABOLISM, CLINICAL MANIFESTATIONS, AND EMERGING THERAPEUTIC STRATEGIES

Abstract

Barth syndrome (BTHS) is a rare, X-linked multi-system disorder caused by pathogenic variants in the TAFAZZIN gene, which encodes the mitochondrial enzyme tafazzin. This enzyme catalyses the remodelling of cardiolipin, a unique phospholipid essential for inner mitochondrial membrane structure and function. The clinical triad of cardiomyopathy, neutropenia, and skeletal myopathy, often accompanied by growth delay and 3-methylglutaconic aciduria, defines the syndrome's phenotypic spectrum. This review analyses the current understanding of Barth syndrome's molecular pathogenesis, from the fundamental defect in cardiolipin remodelling to the diverse mitochondrial dysfunctions that drive tissue-specific pathology. Diagnostic approaches now prioritise the monolysocardiolipin-to-cardiolipin ratio as a robust biochemical marker alongside molecular confirmation. Management remains largely supportive, encompassing cardiac surveillance, infection prevention, nutritional support, and multidisciplinary care. However, the therapeutic landscape is evolving rapidly, with elamipretide recently approved for muscle weakness and promising preclinical studies targeting novel pathways including ABHD18 inhibition and gene therapy. This review highlights how insights from yeast, Drosophila, zebrafish, and murine models have illuminated disease mechanisms and identified therapeutic targets, while emphasizing the critical need for continued research to address remaining questions about phenotypic variability, long-term outcomes, and optimal management strategies.