Anaplerotic Therapy in Propionic Acidemia
Condition: Propionic Acidemia
MeSH terms: Propionic Acidemia; Acidosis; Hyperammonemia
Study type: Interventional
Phase: Phase 1

Summary: 
      The objective of this project is to define whether nutritional supplements (ornithine
      alpha-ketoglutarate, glutamine, or citrate) capable of filling-up the citric acid cycle
      (anaplerotic therapy) can improve hyperammonemia, glutamine levels, and outcome in patients
      with propionic acidemia. Ornithine alpha-ketoglutarate, glutamine, and citrate are commonly
      used as nutritional supplements specially by athletes to increase muscle strength. They can
      be mixed with formula or other foods.
    

Detailed description: 
      Propionic acidemia is caused by deficiency of propionyl CoA carboxylase that impairs the
      supply of succinyl CoA to the citric acid (Krebs) cycle. The Krebs cycle is responsible for
      obtaining energy from food in the form of ATP. ATP is essential for muscle contraction and
      correct functioning of all organs including the hearth, the kidney, and the pancreas.

      Patients with propionic acidemia develop hyperammonemia at birth that recurs during episodes
      of metabolic decompensation. We found that plasma levels of the amino acids
      glutamine/glutamate are reduced in patients with propionic acidemia and decrease, rather than
      increase (like in urea cycle defects or other types of hyperammonemia) with hyperammonemia.
      Since alpha-ketoglutarate is the main source of endogenous glutamate/glutamine synthesis, our
      hypothesis is that chronic hyperammonemia and progressive dysfunction of multiple organs in
      patients with propionic acidemia is due to a functional insufficiency of the citric acid
      (Krebs) cycle with defective production of alpha-ketoglutarate. The basic deficiency of
      intermediates of the Krebs cycle can decrease production of ATP and explain the low muscle
      tone, progressive organ dysfunction, and poor long-term outcome of patients with propionic
      acidemia.

      To test this hypothesis, we will test whether dietary supplementation with alpha
      ketoglutarate precursors (in the form of ornithine alpha ketoglutarate, glutamine or citrate)
      can improve plasma ammonia and overall outcome in patients with propionic acidemia. In this
      study, a limited number of patients (3) with propionic acidemia will be given the 3 different
      nutritional supplements and studied at regular intervals to see whether their
      glutamine/glutamate levels improve and if they have fewer episodes of hyperammonemia or acute
      decompensation. The supplement that produces the best increase in plasma glutamine levels
      will be tested for an additional 30 weeks. Children's development and motor skills will be
      tested before and after therapy to see if there is any improvement. The study will be
      conducted on outpatients at the University of Utah Clinical Research Center. If the initial
      trial is successful, we will try to launch a national trial involving multiple centers in the
      US and abroad to involve the largest number of patients possible.

      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. 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.
    

Intervention name(s): ornithine alpha ketoglutarate; glutamine; disodium citrate
Intervention type(s): Drug; Drug; Drug
Intervention description(s): A dose of 400 mg/kg up to 16 g per day was selected. Split into 2 doses taken for 4 weeks. If determined the drug with the best effect, drug will be taken for 30 weeks.; A dose of 400 mg/kg up to 16 g per day was selected. Split into 2 doses taken for 4 weeks. If determined the drug with the best effects, drug will be taken for 30 weeks.; Dose: 7.5 mEq/Kg or 658 mg/kg up to 16 g per day Split into 2 doses taken for 4 weeks. If determined the drug with the best effects, drug will be taken for 30 weeks.
Other intervention name(s): OKG; Glutamic Acid; Citric Acid Sodium Salt, Sodium Citrate
Intervention MeSH terms: Citric Acid; Sodium Citrate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Propionic Acidemia; hyperammonemia; hypotonia; glutamine; ornithine alpha ketoglutarate; citrate