OBJECTIVE: To explore the results of four types of Urea cycle disorders (UCDs) in newborns from the Xuzhou region, assess the efficacy of newborn screening by tandem mass spectrometry (MS/MS), and analyze their genetic characteristics. METHODS: A retrospective analysis was performed using tandem mass spectrometry to screen for inherited metabolic disorders in 691 712 newborns at the Maternal and Child Health Care Hospital of Xuzhou from November 2015 to December 2023. Ten children (cases 1-10) were diagnosed with Ornithine transcarbamylase deficiency (OTCD), Carbamoylphosphate synthase 1 deficiency (CPS1D), Arginase deficiency (ARGD), and Argininosuccinate synthase deficiency (ASSD) based on MS/MS and genetic testing. This study was approved by the Medical Ethics Committee of Xuzhou Maternity and Child Health Care Hospital (Ethics No.XZFY2024-051K-01J). RESULTS: A total of 691 712 neonates were screened for UCDs using MS/MS, which identified 1 237, 1 237, 510, and 1 009 initial positive cases for OTCD, CPS1D, ASSD, and ARGD, respectively. After genetic testing, 1 case of OTCD, 1 case of CPS1D, 1 case of ASSD, and 7 cases of ARGD were confirmed. The overall positive predictive value for these four UCDs was 0.362%. Among the 10 diagnosed UCD cases, four novel variants were identified, which included OTC: c.1024C>A (p.L342M) and ASS1: c.826A>G (p.M276V), c.695C>T (p.P232L) and c.694C>T (p.P232S). Bioinformatic analysis has rated these as variants of uncertain clinical significance or likely pathogenic based on guidelines from the American College of Medical Genetics and Genomics (ACMG). CONCLUSION The incidence of four UCDs in neonates from the Xuzhou area is relatively low, and there is a correlation between genetic variants and clinical phenotypes. For novel variants with uncertain clinical significance or suspected pathogenicity, their pathogenicity should be clarified in conjunction with clinical and biochemical indicators. The four novel pathogenic variants of UCDs identified in this study have enriched the mutational spectrum of UCDs-associated genes in the Xuzhou region.
Humans ; Infant, Newborn ; Tandem Mass Spectrometry/methods* ; Urea Cycle Disorders, Inborn/diagnosis* ; Neonatal Screening/methods* ; Genetic Testing/methods* ; Female ; Retrospective Studies ; Male ; Ornithine Carbamoyltransferase Deficiency Disease/diagnosis* ; Mutation ; Carbamoyl-Phosphate Synthase (Ammonia)/genetics* ; Ornithine Carbamoyltransferase/genetics*

OBJECTIVE: To explore the genetic basis for a neonate featuring hyperammonemia. METHODS: The patient was examined and tested by tandem mass spectrometry and next generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the proband and her parents. Potential impact of the mutation was predicted with SIFT, PolyPhen-2 and MutationTaste software. RESULTS: Plasma ammonia and alanine were significantly increased in the proband, while serum citrulline was decreased. The neonate was found to harbor compound heterozygous mutations of the CPS1 gene [c.1631C>T(p.T544M) and c.1981G>T(p.G661C)], which were respectively inherited from her father and mother. CONCLUSION The carbamoyl phosphate synthetase I deficiency of the proband can probably be attributed to the mutations of the CPS1 gene. Above finding has expanded the spectrum of CPS1 mutations in association with carbamoyl phosphate synthetase I deficiency.
Carbamoyl-Phosphate Synthase (Ammonia) ; genetics ; Carbamoyl-Phosphate Synthase I Deficiency Disease ; genetics ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperammonemia ; diagnosis ; genetics ; Infant, Newborn ; Mutation

Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 µmol/L; reference range, 11.2-48.2 µmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 µmol/L; reference range, 131-710 µmol/L) and glutamine (5,777 µmol/L; reference range, 376-709 µmol/L), whereas that of citrulline was decreased (2 µmol/L; reference range, 10-45 µmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.
Base Sequence ; Carbamoyl-Phosphate Synthase (Ammonia)/chemistry/*genetics ; Carbamoyl-Phosphate Synthase I Deficiency Disease/diagnosis/*genetics ; Codon, Nonsense ; Exons ; Female ; Frameshift Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Infant, Newborn ; Republic of Korea ; Sequence Analysis, DNA ; Urea Cycle Disorders, Inborn/diagnosis

Carbamoyl-Phosphate Synthase (Ammonia) ; genetics ; Enteral Nutrition ; adverse effects ; Enterocolitis, Necrotizing ; epidemiology ; etiology ; Humans ; Infant, Low Birth Weight ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases ; epidemiology ; etiology ; Multivariate Analysis ; Polymorphism, Single Nucleotide ; Premature Birth ; Risk Factors ; Transfusion Reaction

OBJECTIVETo study the role of carbamyl phosphate I (CPS-I)and ornithine transcarbamoylase (OCT) levels in cirrhosis patients with and without hepatic encephalopathy, and to analyze the correlations between CPS-Iand OCT with the development of hepatic encephalopathy.

METHODSCPS-I, OCT, plasma ammonia and liver function of 95 cirrhosis patients with hepatic encephalopathy and 25 cirrhosis patients without hepatic encephalopathy in our hospital from January 2008 to December 2009 were analyzed. 60 healthy controls were recruited in the control group. The differences of serum CPS-I, OCT levels among the cirrhosis patients with and without hepatic encephalopathy and the healthy controls were analyzed; the correlations of CPS-I, OCT levels with plasma ammonia and total protein in cirrhosis patients,and the correlations of CPS-I, OCT levels with Child-Pugh classification of cirrhosis symptom severity in cirrhosis were analyzed. the clinical characteristics between patients who had HE and no HE with chi-square tests were compared. Comparisons of CPS-I, OCT levels across patients based on the Child-Pugh classification were performed with One-Way ANOVA and Student-Newman-Keuls, correlation of CPS-I, OCT with other indicators were performed with Pearson correlation analysis.

RESULTSSerum CPS-I and OCT levels in cirrhosis patients with hepatic encephalopathy were (143.3+/-48.5) U/L, (297.0+/-102.6) is multiplied by 10 U/L, which were lower than that in cirrhosis patients without hepatic encephalopathy (180.3+/-51.5) U/L, (351.8+/-109.0) is multiplied by 10 U/L (t = 2.53, t = 2.78, P < 0.01). Compared with healthy controls, serum CPS-I and OCT levels in cirrhosis patients with and without hepatic encephalopathy were all lower (t = 3.21, t = 4.16, t = 2.12, t = 3.15, P < 0.05). CPS-I was correlated with OCT, (r = 0.946, P < 0.05); CPS-I and OCT were negatively correlated with ALT and AST (r = -0.284, r = -0.239, r = -0.303, r = -0.322, P < 0.05). Additionally, CPS-I and OCT levels were negatively correlated with the Child-Pugh classification in Cirrhosis (F = 10.13, F = 20.28, P < 0.01).

CONCLUSIONThe serum CPS-I and COT levels were important factors affecting plasma ammonia in patients with cirrhosis and played an important role in the development of hepatic encephalopathy.

Adult ; Ammonia ; blood ; Carbamoyl-Phosphate Synthase (Ammonia) ; metabolism ; Case-Control Studies ; Female ; Hepatic Encephalopathy ; blood ; enzymology ; Humans ; Male ; Middle Aged ; Ornithine Carbamoyltransferase ; metabolism