Clinical Characteristics And Genetic Analysis Of Carbamoyl Phosphate Synthase 1 Deficiency

Background: Carbamoyl phosphate synthetase 1 deficiency(CPS1D)is a rare urea-cycle disorder.Early diagnosis and management is important for good prognosis.The aim of this study was to present the clinical findings,management,biochemical data and molecular genetic analysis of five children with CPS1 D.Methods: The information of five CPS1 D patients were retrospectively studied.We used targeted next-generation sequencing to identify carbamoyl phosphate synthetase 1(CPS1)variants in patients suspected to have CPS1 D.Candidate mutations were validated by Sanger sequencing.In silico and structure analyses was processed for the pathogenicity predictions of the identified mutations.Results: In total 16 patients from the Children's Hospital of Chongqing Medical University were diagnosed as UCDs from January 2014 to January 2019,and 5 of them were CPS1 D patients.Their initial symptoms starting from late neonates to puberty.The clinical manifestations including confusion,gastrointestinal symptoms,psychiatric behavior and seizures.Hyperammonemia were detected in all five patients and the peak blood ammonia were 133.9-366umol/L.Low levels of blood citrulline and no increase in urinary orotic acid were found by LC-MS/MS.The blood ammonia were controlled after the positive treatment combinations,and the patients had good prognosis or left mild to moderate psychomotor retardation.Genetic analysis revealed nine mutations in the PS1 gene,five of which were firstly reported.Seven mutations were missense changes,while the remaining two were predicted to create premature stop codons.In silico and structure analyses showed that these genetic lesions were predicted to block gene expression,interfere the catalytic sites,the internal tunnel,or the regulatory domain,thus affect the function or stability of the enzyme.The overall clinical manifestations and biochemical data of our patient group were consistent with the pathogenic of gene mutations.Conclusion: We reported five cases of CPS1 D who present as typical UCDs manifestations,and five novel mutations of CPS1 gene were found.Mutations of CPS1 have private nature and most of them are missense compound heterozygous.The mutation affecting residue predicted to interfere the gene expression,the catalytic sites,the internal tunnel,or the regulatory domain results in severe phenotype.