Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-L-glutamate

Abstract

Identical studies using stable isotopes were performed before and after a 3-day trial of oral N-carbamyl-l-glutamate (NCG) in 5 subjects with late-onset carbamyl phosphate synthetase deficiency. NCG augmented ureagenesis and decreased plasma ammonia in 4 of 5 subjects. There was marked improvement in nitrogen metabolism with long-term NCG administration in 1 subject.

Figure 1

Biomarkers, including ammonia, urea, glutamine and [¹³C]urea were measured before and after a 3-day trial of N-carbamylglutamate (NCG) 100 mg/kg/d or 2.2g/m²/d if ≥ 25kg. On each study day, after an overnight fast, a baseline sample of heparinized blood was obtained. Then, at time 0, each subject received an enteral dose of [1-¹³C]sodium acetate, dissolved in water. Blood samples were subsequently obtained at 15, 30, 45, 60, 90, 120, 180, and 240 minutes. In subjects ≤ 5 years (subjects 3, 4 and 5), a shortened 120 min protocol was performed, and only samples at 15, 30, 60, and 120 minutes were collected. (From Heibel et al., Hum Mutat. 2011 Oct;32(10):1153-60)

Figure 2

Isotopic enrichment in plasma concentrations of [¹³C]urea in 5 subjects with partial CPS1 deficiency and who were administered 27.5 mg/kg of [1-¹³C]sodium acetate. Subjects ≤ 5 years (subjects 3, 4 and 5) underwent a shortened study, with samples drawn only at time points 0, 15, 30, 60, and 120 minutes.

Figure 3

Plasma levels of ammonia (A), glutamine (B), and urea (C) in the 5 subjects before and after a 3-day treatment with NCG.

Figure 4

In subject 3, the 3-day trial of NCG showed an encouraging biochemical response that a longer trial was planned. Following baseline (day 0) measurement of ammonia, urea, and amino acids, she was prescribed NCG 100 mg/kg/d. When a marked decrease in ammonia and glutamine was again observed, the sodium phenylbutyrate (Buphenyl) daily dose was tapered in 500 mg decrements over the ensuing 6 weeks. In a single instance (day 10), due to parental error, the phenylbutyrate dose was unintentionally reduced by 1500 mg/day, and this error was not identified until the subsequent clinical assessment. She remained clinically well throughout.