Measuring in vivo ureagenesis with stable isotopes.

Stable isotopes have been an invaluable adjunct to biomedical research for more than 70years. Indeed, the isotopic approach has revolutionized our understanding of metabolism, revealing it to be an intensely dynamic process characterized by an unending cycle of synthesis and degradation. Isotopic studies have taught us that the urea cycle is intrinsic to such dynamism, since it affords a capacious mechanism by which to eliminate waste nitrogen when rates of protein degradation (or dietary protein intake) are especially high. Isotopes have enabled an appreciation of the degree to which ureagenesis is compromised in patients with urea cycle defects. Indeed, isotopic studies of urea cycle flux correlate well with the severity of cognitive impairment in these patients. Finally, the use of isotopes affords an ideal tool with which to gauge the efficacy of therapeutic interventions to augment residual flux through the cycle.

Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis.

We studied the effect on ureagenesis of a single dose of N-carbamylglutamate (NCG) in healthy young adults who received a constant infusion (300 min) of NaH(13)CO(3). Isotope ratio-mass spectrometry was used to measure the appearance of label in [(13)C]urea. At 90 min after initiating the H(13)CO3-infusion each subject took a single dose of NCG (50 mg/kg). In 5/6 studies the administration of NCG increased the formation of [(13)C]urea. Treatment with NCG significantly diminished the concentration of blood alanine, but not that of glutamine or arginine. The blood glucose concentration was unaffected by NCG administration. No untoward side effects were observed. The data indicate that treatment with NCG stimulates ureagenesis and could be useful in clinical settings of acute hyperammonemia of various etiologies.

3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a noncompliant child detected through newborn screening.

We report a 19-month-old girl with a 3-methylcrotonyl-coenzyme A carboxylase deficiency that was detected through newborn screening. She was treated for the first 12 months but was lost to follow-up after the initial year. Her parents did not comply with the recommendations for management during periods of illness or for regular medical evaluations. During an acute illness, she presented with severe acidosis, hypoglycemia, and a low plasma carnitine level at 19 months of age. This report highlights the importance of more extensive follow-up plans to improve parental compliance.