Novel Neonatal Variants of the Carbamoyl Phosphate Synthetase 1 Deficiency: Two Case Reports and Review of Literature

Abstract

Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1 . Moreover, our cases and review further support the idea that most (≥90%) of the mutations were “private” and only ∼10% recurred in unrelated families.

CPS1: Looking at an ancient enzyme in a modern light

“…Successful gene therapies have been described for the other enzymes in the urea cycle [137][138][139][140] , and these new studies in CPS1 deficiency lay the groundwork for rescuing the more severe neonatal phenotype in the constitutive knock out and potential clinical translation. With over 250 unique mutations reported, and >90% of them being private mutations 141 (arising in single families only), a successful gene addition approach has the potential to benefit all CPS1 deficiency patients.…”

Novel pathogenic variant (c.2947C > T) of the carbamoyl phosphate synthetase 1 gene in neonatal-onset deficiency

“…To date,hundreds of CPS1D cases have been reported worldwide (Häberle et al, 2011). To our knowledge, the frequency of CPS1D has not been investigated in Chinese cohorts and only eight Chinese patients with CPS1D, including the patient in the present study, have been reported (Chen et al, 2013(Chen et al, , 2018Yang et al, 2017;Zhang et al, 2018;Yan et al, 2019). Table 1 summarizes the results of the present study together with those for seven previously reported Chinese patients.…”

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)(14)(15)(16)(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.…”