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When people think about the heart, most would picture it as a pump that transports blood which delivers nutrients and oxygen to vital organs while simultaneously removing waste and carbon dioxide from them. Much like a water pump, the heart’s efficiency to transport blood can be undermined by plaque accumulating in the blood vessels, which can be resolved by either removing the plaque or bypassing the blockage with another vessel (1). However, unlike a water pump, the human heart is a biological organ that can sometimes automatically increase its muscles’ thickness in cases of faulty genetics, decreasing its efficiency to pump blood. How does one treat the problems caused by these defective genes? This is the question that Dr. Michael Chin and his team have devoted themselves to answering.
Dr. Chin received his PhD and MD at the University of Rochester and currently serves as the inaugural research director for the Tufts Hypertrophic Cardiomyopathy Center and Research Institute. It was during his years as a medical student that he discovered his joy and passion for cardiology which motivated him to apply his knowledge of molecular biology to cardiovascular diseases. In particular, he was interested in examining the pathogenesis of hypertrophic cardiomyopathy in Barth syndrome patients.
Barth syndrome is a rare genetic disorder caused by mutations in the TAZ gene which results in the development of hypertrophic myopathy, or HCM. HCM is an inherited cardiovascular disorder affecting 1 in every 500 people that causes heart muscles to thicken to abnormal proportions. This usually occurs at the septum that separates the right and left ventricles which undermines the heart’s efficiency in transporting blood throughout the body and results in heart failure. In addition to HCM, Barth syndrome also causes skeletal myopathy which is the weakening of skeletal muscles and cyclic neutropenia which is a periodic decrease in the amount of white blood cells. Since the TAZ gene mutation is X-linked, Barth syndrome occurs predominantly in male infants, who often die from either heart failure or acute infections (2).
At this point, one might ask: what is the correlation between the TAZ mutation and Barth syndrome and what methods can be utilized to alleviate the symptoms? The TAZ gene produces a protein called tafazzin which is crucial in catalyzing cardiolipin. A key component of the inner mitochondrial membrane, cardiolipin represents approximately 20% of the total lipid composition and is essential for the optimal functioning of numerous enzymes involved in mitochondrial energy metabolism. Moreover, cardiolipin is the only phospholipid specific to mitochondria and is vital for normal mitochondrial structure and function including electron transport chain assembly to synthesize ATP (2). Adenosine triphosphate, or ATP, provides our cells and organs with a steady source of energy to function efficiently thereby preserving homeostasis within the human body. In Barth syndrome patients, the tafazzin produced by the TAZ mutation abnormally remodels the cardiolipin molecules. Hence, the mitochondria in Barth syndrome patients also become malformed which in turn significantly undermines the production of ATP molecules and subsequently the homeostasis of the human body (3). Dr. Chin further hypothesizes that because cardiovascular muscle cells have a higher density of cristae, the wrinkled folds of a mitochondria’s inner membrane, Barth syndrome patients are more likely to develop HCM since said patients will have more defective mitochondria in their heart muscle cells compared to their healthy counterparts.
Currently, there are no treatment options to cure Barth syndrome, but there are means of mitigating the symptoms. One available method is enzyme replacement therapy where, as the name suggests, the abnormal tafazzin enzyme produced by the TAZ gene mutation is replaced by normal ones via an intravenous injection. However, unlike gene therapy, enzyme replacement therapy offers only a temporary solution since patients must receive periodic intravenous injections of the healthy tafazzin enzyme in order to ensure that they aren’t depleted over time. When inquired why gene therapy isn’t an option, Dr. Chin replied that gene therapy of muscle cells is still unsuccessful and that it might take too long for the correct TAZ gene sequence to replace the TAZ mutation in cardiovascular muscle cells. Hence, potentially jeopardizing the patient’s wellbeing because the patient’s body is unable to produce the healthy tafazzin enzyme on its own when needed.
Despite not being able to cure Barth syndrome, Dr. Chin and his team’s research on Barth syndrome, HCM, and enzyme replacement therapy should be considered a breakthrough in itself since it does offer a treatment option, albeit temporary, to an otherwise still incurable genetic disorder.
References
(1) Coronary heart disease. National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov/health/health-topics/topics/cad. Accessed April 28, 2020.
(2) Chin, Michael T, and Simon J Conway. “Role of Tafazzin in Mitochondrial Function, Development and Disease.” Journal of developmental biology vol. 8,2 10. 23 May. 2020.
(3) Paradies, Giuseppe et al. “Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects.” Cells vol. 8,7 728. 16 Jul. 2019.
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