Master of Science

thesisPropionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme that converts propionyl-CoA to methylmalonyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which sequesters oxaloacetate from the Krebs cycle to form methylcitric acid. This may lead to a deficiency in Krebs cycle intermediates. Our study looked at whether adding glutamate, citrate, or ornithine α-ketoglutarate (chemicals that could fill up the Krebs cycle as anaplerotic agents) to patients' diets affected plasma levels of glutamine and ammonia, and the urinary excretion of Krebs cycle intermediates. We also looked at developmental markers and hospitalizations to determine clinical efficacy. Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period. Levels of Krebs cycle intermediates, α-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation. Glutamine levels did not decrease with increasing ammonia levels. Glutamate and alanine levels significantly increased, rather than decreased with increasing ammonia levels. There was a significant direct correlation between lysine and ammonia. Hospitalizations per year decreased significantly in the 2 years following the study compared to the 2 years before and during the study. These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: -ketoglutarate, succinate and fumarate. Citrate supplements appear to be a safe and might have contributed to reducing hospitalizations in patients with propionic acidemia