Short-Term Outcome of Propionic Aciduria Treated at Presentation with N-Carbamylglutamate: A Retrospective Review of Four Patients

Abstract

N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 mM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 mM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 mM (740 and 1,572) and their levels fell below 500 mM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.

Carglumic acid for the treatment ofN-acetylglutamate synthase deficiency and acute hyperammonemia

“…Most published reports on neonatal patients with MMA or PA describe carglumic acid doses ranging from 100 to 250 mg/kg bw resulting in a rapid decrease of plasma ammonia levels [26,27,29,51,52,[65][66][67]. In a single MMA patient with neonatal hyperammonemia unresponsive to standard treatment, plasma ammonia levels after a loading dose of carglumic acid (70 mg/kg) dropped by 300 µmol/l/h and normalized after 3 h to <100 µmol/l [29].…”

“…The use of carglumic acid for treatment of acute hyperammonemia secondary to organic acidurias has been reported in a small number of case reports [26][27][28][29][30]51,52,65] and was also discussed based on isotope studies in healthy volunteers [64]. Most published reports on neonatal patients with MMA or PA describe carglumic acid doses ranging from 100 to 250 mg/kg bw resulting in a rapid decrease of plasma ammonia levels [26,27,29,51,52,[65][66][67].…”

N-Carbamylglutamate Is an Effective Treatment for Acute Neonatal Hyperammonaemia in a Patient with Methylmalonic Aciduria

“…NCG has recently been used as part of a multiple treatment strategy for hyperammonaemia in MMA [5,6,7] and in other classical organic acidurias such as propionic aciduria [6,7,11,12,13,14] and isovaleric aciduria [15]. Kasapkara et al [15] reported on the use of NCG in the treatment of hyperammonaemia in a 3-day-old neonate with decompensated isovaleric aciduria with a single dose of NCG 150 mg/kg.…”

Efficacy of N-carbamoyl-L-glutamic acid for the treatment of inherited metabolic disorders

“…However, the use of these medications in organic acidemias is controversial. While no controlled studies have been performed, some reported cases suggest that scavenger medications may have limited effectiveness to lower ammonia levels during acute hyperammonemic crisis in children in PA [43–45]. Therefore, currently proposed guidelines for the management of MMA and PA caution that phenylbutyrate/phenylacetate should be used with extreme caution and should be discontinued once the diagnosis of MMA and PA is established [46].…”