Anaplerotic therapy in propionic acidemia

Abstract

Background Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. Purpose The objective of this study was to determine whether supplements with glutamine (400 mg/kg per day), citrate (7.5 mEq/kg per day), or ornithine α-ketoglutarate (400 mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia. Methods 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 and then for a 2 year extension. Results The urinary excretion of the Krebs cycle intermediates, α-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2 years following the study (when citrate was continued) compared to the 2 years before and during the study. Conclusions These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: α-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

Propionyl-CoA carboxylase – A review

“…Moreover, understanding of the gene and enzyme structure has brought to our attention a number of possible gene therapies which are currently being studied in mice [117–119]. The field continues to explore the impact of antioxidants [79] and anaplerotic supplementation [120]. …”

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…Moreover, the therapeutic window of opportunity and the target tissue(s) are, to date, still not sufficiently understood. 5 In summary, to further improve survival rate and, equally important, quality of life of PA and MMA patients, there is a need for systematic (re-)evaluation of each and everyone of the accepted and potential treatment strategies, ideally in (large) randomized clinical trials 109 but if that is not feasible, in smaller trials 85 or on an individual patient basis, 1,3 so that we can better determine who will benefit when and how from which treatment strategy.…”

Practical management of organic acidemias

“…Some work has been done to examine whether replacement of these intermediates could be helpful in the propionate pathway OAs. Recent studies have shown that citrate supplements can replace some missing downstream intermediates in individuals with PA or MMA, but not necessarily other compounds [29].…”