The urea cycle is a cycle of biochemical reactions that take place in the liver to convert toxic ammonia in the blood (a product of protein metabolism) to non-toxic urea. Patients with N-acetylglutamate synthase (NAGS) deficiency lack an enzyme that makes N-acetylglutamate (NAG) needed for the cycle to function and are, thus, unable to effectively remove ammonia from the blood. A build up of toxic ammonia in the blood can cause brain damage or even death. The drug N-carbamylglutamate (abbreviated as NCG or referred to as brand name Carbaglu®) has been used to take the place of NAG in the urea cycle making the urea cycle functional again and able to remove toxic ammonia more effectively.
The goal of this research project is to test the effect of N-carbamylglutamate on ureagenesis (urea production) in patients with four other inherited metabolic diseases that cause hyperammonemia (high ammonia levels) including: carbamyl phosphate synthetase I (CPSI) deficiency (CPSD), Ornithine transcarbamylase (OTC) deficiency (OTCD), propionic acidemia (PA) and methylmalonic acidemia (MMA). Researchers hope to find out whether NCG will significantly increase or restore urea production in these patients by providing a replacement for NAG.
Researchers will measure the difference in urea production before and after taking NCG. This will let them know whether or not NCG is increasing conversion of ammonia to urea.
Researchers will also measure levels of ammonia, urea and glutamine in the blood before and after taking NCG. For participants with OTCD, we will also look at orotate and or orotidine levels in the urine before and after taking NCG.
Together, these tests would determine whether NCG could be effective in the treatment of hyperammonemia (high ammonia levels) in these conditions.
About this Study
Patients of all ages, newborns and up, with any of the four disorders are eligible to participate in the study. Following an overnight fast, participants will drink a solution containing [1-13C] sodium acetate, a salt made from vinegar. This chemical is harmless and allows us to track urea production. Blood samples will be obtained over 2-4 hours (depending on patient's age) after the participant drinks the [1-13C] sodium acetate, and plasma ammonia, urea, glutamine (also urine orotate and orotidine for participants with OTCD), and [13C] urea will be measured.
Participants will then take NCG (a tablet that can be dissolved in water) for 3 days, and then will repeat the same procedure as on the first day.
You are eligible to participate if you have been diagnosed with one of the following inborn errors of metabolism:
- partial (late onset) carbamyl phosphate synthetase I deficiency (CPSD)
- partial (late onset) ornithine transcarbamylase deficiency (OTCD)
- neonatal onset propionic acidemia (PA)
- neonatal onset methylmalonic acidemia (MMA)
You are not eligible to participate if:
- Are acutely ill on the day of the study
- Are pregnant or breastfeeding
- Have an altered mental status, are lethargic or comatose
- Have hyperammonemia caused by other urea cycle disorders, lysinuric protein intolerance, mitochondrial disorders, congenital lactic academia, fatty acid oxidation defects or primary liver disease
- Have a hemoglobin level of less than 9 g/dl
- Have taken NCG within a week of participation in the study
How to participate
In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.
Children's National Medical Center
Study Coordinator: Leslie M Atley
PI: Nicholas Ah Mew, MD
Study Coordinator: Leslie M Atley