Barth syndrome: cardiolipin, cellular pathophysiology, management, and novel therapeutic targets

Barth syndrome is a rare X-linked genetic disease classically characterized by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia, and 3-methylglutaconic aciduria. It is caused by mutations in the tafazzin gene localized to chromosome Xq28.12. Mutations in tafazzin may result in alterations in the level and molecular composition of the mitochondrial phospholipid cardiolipin and result in large elevations in the lysophospholipid monolysocardiolipin. The increased monolysocardiolipin:cardiolipin ratio in blood is diagnostic for the disease, and it leads to disruption in mitochondrial bioenergetics. In this review, we discuss cardiolipin structure, synthesis, and function and provide an overview of the clinical and cellular pathophysiology of Barth Syndrome. We highlight known pharmacological management for treatment of the major pathological features associated with the disease. In addition, we discuss non-pharmacological management. Finally, we highlight the most recent promising therapeutic options for this rare mitochondrial disease including lipid replacement therapy, peroxisome proliferator-activated receptor agonists, tafazzin gene replacement therapy, induced pluripotent stem cells, mitochondria-targeted antioxidants and peptides, and the polyphenolic compound resveratrol.