N‐carbamoylglutamate‐responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects

Abstract

N ‐carbamoyl‐ l ‐glutamate (NCG), the N ‐acetyl‐ l ‐glutamate analogue used to treat N ‐acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG‐responsiveness could be mutation‐specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity ( V max ; ~2‐fold reduction), and apparent affinity (~5‐fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.

Short communication: Effects of dietary N-carbamoylglutamate supplementation on the milk amino acid profile and mozzarella cheese quality in mid-lactating dairy cows

“…Wu et al (2015) demonstrated that NCG is a nontoxic substance with no genotoxicity; therefore, the milk with NCG would be a safe product for humans. Previous studies showed that supplementation with NCG could improve liver function and intestinal health and alleviate oxidative stress in animals (Cao et al, 2016;Xiao et al, 2016;Zhang et al, 2019); additionally, it is used to treat hyperammonemia in rare inherited disorders, such as carbamoyl phosphate synthetase I and N-acetylglutamate synthase deficiency, ornithine transcarbamylase deficiency, and methylmalonic acidemia (Tuchman et al, 2008;Yap et al, 2019). The underlying mechanism may be that NCG promotes endogenous synthesis of Arg (Wu et al, 2004(Wu et al, , 2010, and this was also reflected in our previous study (Gu et al, 2018).…”

Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature

“…While a response to carbamylglutamate aids in the diagnosis, it is not in itself diagnostic of NAGS deficiency, as carbamylglutamate has been shown to be effective in some cases of other inherited metabolic disorders by augmenting ureagenesis and decreasing plasma ammonia, including CPS1 deficiency, ornithine transcarbamylase (OTC) deficiency, citrullinemia type I (argininosuccinic acid synthetase deficiency), methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), carbonic anhydrase VA (CAVA) deficiency, and multiple acyl-CoA dehydrogenase deficiency (MADD). Carbamylglutamate has been used in acute treatment of hyperammonemia in some cases of CPS1 deficiency [47][48][49], OTC deficiency [50], PA [51][52][53][54][55], MMA [51][52][53][54][55][56], IVA [57], CAVA deficiency [58,59], and MADD [60] as well as long-term management of some cases of CPS1 deficiency [48,61], citrullinemia type I [62], OTC deficiency [50], PA [63,64], MMA [64], and MADD [60].…”

Therapeutic effect of N-carbamylglutamate in CPS1 deficiency

“…The protein structure and function of CPS1 has been determined by De Cima et al [ 16 ]. Yap et al reported that structural changes in CPS1 protein caused by mutations in CPS1, decrease the stability of the protein or lower the affinity of the mutant enzyme for NAG [ 17 ]. Furthermore, they found that NCG may improve these conditions [ 17 ].…”

“…Yap et al reported that structural changes in CPS1 protein caused by mutations in CPS1, decrease the stability of the protein or lower the affinity of the mutant enzyme for NAG [ 17 ]. Furthermore, they found that NCG may improve these conditions [ 17 ]. The quantity of CPS1 protein encoded by CPS1 missense variants may be highly diverse [ 18 ].…”

“…The quantity of CPS1 protein encoded by CPS1 missense variants may be highly diverse [ 18 ]. NCG can have different effects, including adverse effects on ureagenesis, depending on the type of CPS1 mutation [ 17 ]. Genetic analysis and evaluation of ammonia levels after initiation of NCG treatment are important.…”