ABSTRACT
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.
