Anaplerotic therapy in Propionic Acidemia

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DESCRIPTION (provided by applicant): The objective of this project is to define whether nutritional supplements capable of filling-up the citric acid cycle (anaplerotic therapy) can improve hyperammonemia, glutamine levels, and outcome in patients with propionic acidemia. Propionic acidemia is a rare recessive disorder caused by deficiency of propionyl CoA carboxylase. Deficient activity of propionyl CoA carboxylase impairs the supply of succinyl CoA to the citric acid cycle. Affected patients develop hyperammonemia at birth that recurs during episodes of metabolic decompensation. The investigators have found that plasma levels of glutamine/glutamate are reduced in patients with propionic acidemia and decrease, rather than increase, with hyperammonemia. Since a-ketoglutarate is the main source of endogenous glutamate/glutamine synthesis, their hypothesis is that chronic hyperammonemia in patients with propionic acidemia is due to a functional insufficiency of the citric acid (Krebs) cycle with defective production of a-ketoglutarate. The basic deficiency of intermediates of the Krebs cycle could decrease production of ATP and explain the low muscle tone, progressive organ dysfunction, and poor outcome of patients with propionic acidemia. To test this hypothesis, the investigators will determine whether dietary supplementation with a-ketoglutarate precursors (in the form of ornithine a-ketoglutarate, glutamine, or citrate) can improve plasma ammonia and overall outcome in patients with propionic acidemia. The current therapy of propionic acidemia is based on restriction of precursors of propionic acid (methionine, valine, isoleucine, threonine, odd chain fatty acids, cholesterol) and administration of carnitine to help remove toxic organic acids. This therapy is not effective in preventing the long-term complications of the disease, even in children identified at birth by newborn screening. Thus this research will test a completely new way of treating patients with severe and disabling metabolic disorders using replacement of downstream products involved in the generation of energy (ATP). This approach, if effective, could be extended to a number of other diseases, including other organic acidemias and mitochondrial disorders.