Barth syndrome (BTHS) is a genetic, X-linked, rare but often fatal, pediatric 
skeletal- and cardiomyopathy occurring due to mutations in the tafazzin gene 
(TAZ). TAZ encodes a transacylase involved in phospholipid biosynthesis, also 
called tafazzin, which is responsible for remodeling the inner mitochondrial 
membrane phospholipid, cardiolipin (CL). Tafazzin mutations lead to 
compositional alterations in CL molecular species, causing extensive 
mitochondrial aberrations and ultrastructural muscle damage. There are no 
specific treatments or cure for BTHS. Current therapy is largely palliative and 
aimed at treatment of organ-specific complications during disease progression. 
Polypharmacy frequently occurs during treatment and may lead to severe adverse 
events. Adverse reactions may originate from exogenous factors such as the 
inadvertent co-administration of contraindicated drugs. Theoretically, 
endogenous factors such as polymorphic variations in genes encoding drug 
metabolizing enzymes may also precipitate fatal toxicity. Investigation of the 
consequences of pharmacogenomic variations on BTHS therapy is lacking. To our 
knowledge, this review presents the first examination of the possible sources of 
pharmacogenomic variations that may affect BTHS therapy. We also explore 
BTHSspecific patents for possible treatment options. The patents discussed 
suggest innovative strategies for treatment, including feeding linoleic acid to 
patients to overcome compositional CL deficiency; or the use of 2S,4R 
ketoconazole formulations to augment CL levels; or the delivery of mitochondrial 
stabilizing cargo. Future research directions are also discussed.