Author: Sean Krivitsky ‘26

Barth syndrome is a rare, severe genetic disorder that primarily affects muscle development and the heart’s ability to efficiently pump blood. It is most common in males given that it is an X-linked disorder and it is known to significantly reduce life expectancy. Despite the severity of Barth syndrome, there are limited therapies available to treat this disease. This condition is caused by alterations in the metabolism of lipids resulting from a mutation in the tafazzin (TAZ) gene. This mutation in TAZ induces decreased production of a lipid that is important for energy metabolism and causes the hallmark symptoms of the disorder. Research led by Dr. Valerian E. Kagan and co-authored by researchers in the Bahar lab at Stony Brook University provides further insights into the mechanism by which TAZ mutations contribute to the development of Barth syndrome as well as a therapeutic solution to help treat this life-altering condition.

The Bahar group, along with other collaborators, revealed that the pathogenic mechanism of Barth syndrome involves the formation of an abnormal protein complex with activity that drives reactions in the mitochondria. These reactions ultimately result in the production of specific molecules called peroxidized CL molecules that are known signals for the onset of controlled cell death and have also been found to disrupt important cellular pathways. Specifically, this signal can disrupt mitochondrial function, which is implicated in the pathology of Barth syndrome.

By identifying the mechanism by which TAZ mutations contribute to the phenotype of Barth syndrome patients, these researchers were then able to identify an important inhibitor capable of inhibiting the abnormal protein complex that contributes to Barth syndrome development, called IOA. IOA, and a derivative named TPP-IOA that specifically targets the mitochondria of cells, can inhibit the aforementioned irregular protein complex, which downregulates the amount of cell death signals and disruption of various cellular pathways. This inhibitor was demonstrated to reduce the presence of Barth syndrome symptoms in a Drosophila melanogaster animal model. Ultimately, this research provides important insights into a previously unknown mechanism by which Barth syndrome develops and points to a therapeutic inhibitor capable of treating the disease.

Figure 1. Images of children displaying hallmark facial features related to the development of Barth syndrome.

Works Cited

1. Kagan, V. E., Tyurina, Y. Y., Mikulska-Ruminska, K., Damschroder, D., Vieira Neto, E., Lasorsa, A., Kapralov, A. A., Tyurin, V. A., Amoscato, A. A., Samovich, S. N., Souryavong, A. B., Dar, H. H., Ramim, A., Liang, Z., Lazcano, P., Ji, J., Schmidtke, M. W., Kiselyov, K., Korkmaz, A., … Greenberg, M. L. (2023). Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome. Nature Metabolism, 5(12), 2184–2205. https://doi.org/10.1038/s42255-023-00926-4 
2. Image retrieved from: Wikimedia | Barth Syndrome Consistent Facial Features of Boys (Orphanet Journal of Rare Diseases Clarke et al)