N-carbamylglutamate can potentially improve hyperammonemia in patients with propionic and methylmalonic acidemia

N-acetylglutamate (NAG) is a chemical produced in the liver that is essential for normal function of the urea cycle; without it, the cycle does not do its job of detoxifying ammonia.  Patients who are deficient in NAG in the liver develop hyperammonemia. There are several causes for NAG deficiency. The most obvious is a genetic defect in N-acetylglutamate synthase (NAGS), the enzyme that produces NAG.  Other causes involve secondary NAG deficiency due to interference with its production by NAGS.  The most known cause for secondary NAG deficiency is propionic acidemia (PA) where the accumulation of propionyl-CoA in liver mitochondria interferes with NAG production.  Methylmalonic acidemia (MMA) presumably manifests the same problem.  Similarly, patients treated with valproic acid may also develop low liver NAG due to interference with NAG production by valproic acid metabolites.  All latter conditions are associated with hyperammonemia presumably due to NAG deficiency.  Since we have recently shown that the drug Carbaglu® (N-carbamylglutamate) restores to normal urea cycle functions and eliminates the hyperammonemia in patients with NAGS deficiency, we further hypothesize that patients with PA and MMA who have hyperammonemia may also benefit from this drug.  In order to investigate this hypothesis, we have launched a study in patients with severe PA and MMA (those who presented with neonatal hyperammonemia).  The study is open to patients with severe PA or MMA who are 5 years and older and consists of oral administration of a stable isotope [13C]sodium acetate before, and following 3 days of Carbaglu treatment, comparing the amount of [13C] that ends up in urea as an indication of urea production rate.  One patient with PA who was studied showed a marked increase of urea production on Carbaglu as well as decrease in glutamine and glycine levels.  If this finding can be reproduced in additional patients with PA or MMA, it will suggest that Carbaglu could effectively treat hyperammonemia episodes in patients with the most common organic acidemias. Although hyperammonemia is only one of the several mechanisms of metabolic derangement in PA or MMA, alleviation of hyperammonemia could facilitate the management of these patients.

If you are interested in being part of this study, please contact paf@pafoundation.com.