Anaplerotic therapy in propionic acidemia

Area of Science:

• Biochemistry
• Metabolic Disorders
• Clinical Nutrition

Background:

• Propionic acidemia is a rare metabolic disorder due to propionyl-CoA carboxylase deficiency.
• This deficiency impairs propionic acid metabolism, leading to methylcitric acid accumulation and citric acid cycle intermediate depletion.
• Patients cannot effectively metabolize propionic acid, impacting cellular energy production.

Purpose of the Study:

• To evaluate the efficacy of glutamine, citrate, or ornithine α-ketoglutarate as anaplerotic agents in propionic acidemia.
• To assess the impact of these supplements on plasma amino acid levels, urinary Krebs cycle intermediates, and clinical outcomes.
• To identify the most effective anaplerotic agent for managing propionic acidemia.

Main Methods:

• Three patients with propionic acidemia received daily supplements of glutamine, citrate, or ornithine α-ketoglutarate for four weeks each, with washout periods.
• The most effective supplement was administered for an extended period (30 weeks) followed by a 2-year extension.
• Urinary excretion of Krebs cycle intermediates and plasma levels of glutamine and ammonia were monitored.

Main Results:

• Citrate supplementation significantly increased urinary excretion of Krebs cycle intermediates (α-ketoglutarate, succinate, fumarate).
• No significant changes in ammonia or glutamine levels were observed, but glutamate and alanine levels increased, normalizing ammonia buffering.
• Hospitalizations decreased significantly in the 2 years following citrate supplementation compared to before and during the trial.

Conclusions:

• Citrate acts as an effective anaplerotic agent, replenishing downstream citric acid cycle intermediates in propionic acidemia.
• Citrate supplementation is safe and may contribute to a reduction in hospitalizations for patients with propionic acidemia.
• Anaplerotic therapy with citrate shows potential for improving clinical outcomes in propionic acidemia.