Stable isotopes in the diagnosis and treatment of inherited hyperammonemia

Abstract

Stable isotopes have greatly contributed to our understanding of nitrogen metabolism and the urea cycle. The measurement of urea flux via isotopic methods has traditionally been utilized to determine total body protein synthesis in subjects with an intact urea cycle. However, isotopic studies of nitrogen metabolism are also a useful adjunct to conventional clinical investigations in the diagnosis and management of the inherited hyperammonemias. Such studies offer a safe non-invasive method of measuring the reduction of in vivo hepatic ureagenesis, and thus may provide a more accurate measure of phenotypic severity in affected patients. In addition, isotopic methods are ideally suited to evaluate the efficacy of novel therapies to augment urea production.

Keywords: Stable isotopes; mass spectrometry; urea cycle disorders; ureagenesis.

Figure 1

Isotopic enrichment in plasma ¹³CO₂ (A), and plasma concentrations of [¹³C] urea (B) in 7 patients with propionic acidemia who were administered 27.5 mg/kg of [¹³C] sodium acetate before and after 3d NCG therapy.

Figure 2

Increase over time in isotopic enrichment of [¹³C]urea (A) and plasma concentration of [¹³C]urea (B) in a patient with a suspected proximal urea-cycle disorder, who was administered 27.5 mg/kg of [1-¹³C]sodium acetate before and after a 3d trial of NCG. Molecular and enzymatic testing had failed to reveal a diagnosis. However, the marked augmentation in urea production following an NCG trial shown here prompted a search in the non-coding regions of the NAGS gene, and culminated in the identification of a mutation in the NAGS enhancer [38].