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

Beibei Yan,Zhongtao Gai,Yi Liu,Chao Wang,Yuqiang Lv,Min Gao,Kaihui Zhang,Haiyan Zhang,Xiaoying Li

doi:10.3389/fgene.2019.00718

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.

Highlights

Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder, characterized by hyperammonemia with the incidence of 1/50,000 to 1/300,000 (Díez-Fernández et al, 2015)
Two patients from two unrelated families who were from the neonatal intensive care unit (NICU) of Qilu Children’s Hospital of Shandong University (QCHSU) were firstly screened by LC/ MS-MS and gas chromatography mass spectrometry (GC/MS)
Her mother had regular prenatal care starting from 12 weeks of pregnancy. She was apparently healthy at birth with weight of 2.95 kg, Apgar score of 10 at 1 min and 5 min after birth. The following day, she had a fever, and gradually developed hyporeactiveness presenting respiratory distress, seizures, and acute circulatory collapse so she was immediately transported to NICU in QCHSU from local hospital

Summary

Introduction

Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder, characterized by hyperammonemia with the incidence of 1/50,000 to 1/300,000 (Díez-Fernández et al, 2015). CPS1D is currently divided into two types of neonatal onset and late onset, whereas CPS1D with severe manifestations of hyperammonemia is common in neonatalonset patients (Choi et al, 2017; Rokicki et al, 2017; Yang et al, 2017; Zhang et al, 2018). The neonatal-onset patient with CPS1D appears to be healthy at birth, but deteriorates rapidly into severe hyperammonemia, presenting poor feeding, vomiting, hypotonia, irritability, seizures, hypothermia, lethargy, coma, apnea, and even death after first feeding (Funghini et al, 2012; Choi et al, 2017; Rokicki et al, 2017; Zhang et al, 2018). CPS1 catalyzes the initial and limiting step of the urea cycle, which is critical in the detoxification of excess ammonia, so CPS1D patient suffering from hyperammonemia will present a decreased level of citrulline but elevated glutamine in blood amino acid analysis, and a low level of orotic acid in urine test (Funghini et al, 2012; de Cima et al, 2015; Ali et al, 2016).

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