Barth syndrome is caused by mutations in a gene called **TAFAZZIN**, which is located on the X chromosome. This gene provides instructions for making a protein named tafazzin, which plays a crucial role in maintaining the health and function of mitochondria, the energy-producing structures inside cells. Specifically, tafazzin is involved in remodeling a unique fat molecule called **cardiolipin**, found in the inner membrane of mitochondria. Cardiolipin is essential for the proper structure and function of mitochondria, especially in tissues that require a lot of energy, such as the heart and skeletal muscles.
When the TAFAZZIN gene is mutated, the tafazzin protein either does not function properly or is produced in insufficient amounts. This leads to abnormal cardiolipin composition and accumulation of immature forms of cardiolipin, disrupting mitochondrial membranes and impairing their ability to generate energy efficiently. As mitochondria become dysfunctional, cells in high-energy-demand tissues suffer, causing the symptoms seen in Barth syndrome.
The defective cardiolipin remodeling affects mitochondrial bioenergetics—the process by which mitochondria produce ATP, the energy currency of the cell. This disruption leads to problems such as **dilated cardiomyopathy** (a weakened and enlarged heart muscle), skeletal muscle weakness, and neutropenia (a low number of a type of white blood cell important for fighting infections). The heart muscle, in particular, is severely affected because it relies heavily on mitochondrial energy production to function properly.
In addition to the direct effects on mitochondria, the mutation in TAFAZZIN can cause secondary cellular problems. For example, the accumulation of immature cardiolipin and related molecules may alter protein synthesis within mitochondria, potentially reducing overall energy demands as a compensatory mechanism. However, these compensations are not permanent and contribute to the progressive nature of the disease.
Barth syndrome is inherited in an X-linked manner, meaning the mutated gene is on the X chromosome. Since males have only one X chromosome, a single defective copy of the TAFAZZIN gene causes the disease. Females, having two X chromosomes, are typically carriers and usually do not show symptoms because their second X chromosome can compensate.
Recent research has also identified other genes and enzymes, such as **ABHD18**, that interact with the cardiolipin biosynthesis pathway and mitochondrial function. These discoveries open new avenues for potential therapies aimed at restoring mitochondrial health by targeting these additional molecules.
In summary, Barth syndrome arises from mutations in the TAFAZZIN gene that disrupt the remodeling of cardiolipin, leading to mitochondrial dysfunction. This mitochondrial impairment primarily affects the heart and muscles, causing the characteristic symptoms of the syndrome. The complex interplay between defective cardiolipin, mitochondrial bioenergetics, and cellular compensatory mechanisms underlies the disease’s progression and severity.
