Therapeutic effect of N-carbamylglutamate in CPS1 deficiency

Abstract

The detoxification of ammonia to urea requires a functional hepatic urea cycle, which consists of six enzymes and two mitochondrial membrane transporters. The initial step of the urea cycle is catalyzed by carbamyl phosphate synthetase 1 (CPS1). CPS1 deficiency (CPS1D) is a rare autosomal recessive disorder. N -Carbamylglutamate (NCG), a deacylase-resistant analogue of N -acetylglutamate, can activate CPS1. We describe the therapeutic course of a patient suffering from neonatal onset CPS1D with compound heterozygosity for the c.2359C > T (p.Arg787*) and c.3559G > T (p.Val1187Phe) variants in CPS1 , treated with NCG. She presented with hyperammonemia, which reached 944 μmol/L at the age of 2 days. The ammonia concentration decreased after treatment with continuous hemodiafiltration, NCG, sodium benzoate, sodium phenylbutyrate, L-arginine, vitamin cocktail (vitamin B1, vitamin B12, vitamin C, vitamin E, biotin), l -carnitine, coenzyme Q10, and parenteral nutrition. Her ammonia and glutamine levels remained low; thus, protein intake was increased to 1.2 g/kg/day. Furthermore, the amount of sodium benzoate and sodium phenylbutyrate were reduced. She remained metabolically stable and experienced no metabolic crisis following treatment with oral NCG, sodium benzoate, sodium phenylbutyrate, citrulline, vitamin cocktail, l -carnitine, and coenzyme Q10 until she underwent liver transplantation at 207 days of age. She had no neurological complications at the age of 15 months. Ammonia and glutamine levels of the patient were successfully maintained at a low level via NCG treatment with increased protein intake, which led to normal neurological development. Thus, undiagnosed urea cycle disorders should be treated rapidly with acute therapy including NCG, which should be maintained until a genetic diagnosis is reached. It is essential to prevent metabolic crises in patients with CPS1D until liver transplantation to improve their prognoses.

A 36-year-old Man with Repeated Short-term Transient Hyperammonemia and Impaired Consciousness with a Confirmed <i>Carbamoyl Phosphate Synthase 1</i> Gene Monoallelic Mutation

“…According to previous studies, a few cases of CPS1 deficiency with only a single-allele mutation have been reported ( Table 2 ) ( 13 - 17 ). Further studies are needed to determine whether or not this patient has mutations in the other alleles that could not be detected through conventional genetic analyses or whether the slightly low CPS1 activity in this patient was further reduced by some acquired factors.…”

Novel compound heterozygote variants: c.4193_4206delinsG (p.Leu1398Argfs*25), c.793C > A (p.Pro265Thr), in the CPS1 gene (NM_001875.4) causing late onset carbamoyl phosphate synthetase 1 deficiency—Lessons learned

“…CPS1 gene variants may decrease the stability of the CPS1 protein or lower the affinity of the enzyme for NAG [ 18 ]. Therefore, NCG supplementation may improve CPS1 function in some patients through saturation of NAG sites in partial CPS1 deficiency, maximizing CPS1 activation and protecting CPS1 from thermal and proteolytic inactivation [ 2 , 19 ]. However, in other CPS1 variants, NCG may compete with NAG binding instead and decrease residual ureagenesis [ 20 ].…”

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].…”