The
Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane
phospholipids,
lactic acidosis, organic
acid-uria, skeletal muscle weakness and
cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a
phospholipid transacylase that promotes
cardiolipin acyl chain remodeling. Absence of tafazzin activity results in
cardiolipin molecular species heterogeneity, increased levels of
monolysocardiolipin and lower
cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in
cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via
NADH ubiquinone oxidoreductase activity leads to a buildup of
NADH in the matrix space and product inhibition of key TCA cycle
enzymes. As TCA cycle activity slows
pyruvate generated by glycolysis is diverted to
lactic acid. In turn, Cori cycle activity increases to supply muscle with
glucose for continued
ATP production.
Acetyl CoA that is unable to enter the TCA cycle is diverted to organic
acid waste products that are excreted in urine. Overall, reduced
ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in
ATP production capacity underlies cell and tissue pathology that ultimately is manifest as
dilated cardiomyopathy.