Clinical trial of N-carbamoyl-L-Glntamic acid in two patients with late-onset ornitine transcarbamirase deficiency (OTCD).

Background: N-acetylGlntamate (NAG) is an essential cofactor for carbamoylphosphate synthetase 1 (CPS1), the first enzyme of urea cycle. Recently, N-carbamoyl-L-Glntamic acid (NCG) is used in not only NAG synthetase deficiency and organic acidemia but also in some patients with partial CPS1 deficiency and metabolic stroke due to OTCD. Here we presented clinical trial of NCG in two patients with late-onset OTCD with approval by the Clinical Research Ethics Committee.

Methods: Patient 1 is 9-year-old girl diagnosed at age 1 and attending regular classes. Patient 2 is 15-year-old girl who developed hyperammonemic encephalopathy (NH3: 2000 μg/dl) at age 2 and is bedridden. NCG of 100 mg/kg/day was administered orally or via a gastrostomy daily for 4 weeks. Other chronic phase treatment was continued. The endpoints were, 1) Short-term; changes in blood NH3, Glntamine (Gln) levels from baseline to 3, 5 and 24 hours after the NCG administration, 2) Long-term; changes in blood NH3, Gln levels from baseline to Day 5, 8, 15, 22, and 29, and comparison of mean NH3 and Gln levels between before, during and after trial, 3) Safety; changes in clinical symptoms and biochemical tests.

Result: No adverse events were observed during the study period and subsequent observations. In both patients, no postprandial NH3 elevation was observed with NCG. In patient 1, plasma Gln level showed mild decreases during long-term administration. On the other hand, no change was observed in patient 2.

Discussion: NCG enhances urea synthesis by increasing flux through CPS1 in even healthy control. We hypothesized that NCG can enhance urea synthesis by increasing binding of carbamoylphosphate to OTC and reduce Gln by driving the formation of orotic acid in the cytosol. However, this study could not demonstrate the clear effect of NCG on late-onset OTCD. Further study would be needed to show the effect of NCG. (This study was supported by Recordati Rare Diseases Japan.)