The Application of Next-Generation Sequencing (NGS) in Neonatal-Onset Urea Cycle Disorders (UCDs): Clinical Course, Metabolomic Profiling, and Genetic Findings in Nine Chinese Hyperammonemia Patients

Biomed Res Int. 2020 Aug 31:2020:5690915. doi: 10.1155/2020/5690915. eCollection 2020.

Abstract

During Jan. 2016-Dec. 2019, nine Chinese patients from eight unrelated families were diagnosed with neonatal-onset UCDs by targeted panel sequencing or whole-exome sequencing (WES). Their clinical manifestations, biochemical features, 180-day-age outcomes, and molecular genetic characteristics were reviewed retrospectively. NGS-based tests revealed 7 patients diagnosed with ornithine transcarbamylase deficiency (OTCD) and 2 with carbamoylphosphate synthetase I deficiency (CPS1D). The spectrum of the clinical presentation of nine affected individuals progressed from unspecific symptoms like poor feeding to somnolence, coma, and death. All patients presented with an acute hyperammonemia. The most robust metabolic pattern in OTCD was hyperglutaminemic hyperammonemia with high concentration of urine orotic acid, and it was reported in six patients. Of ten variants found on the OTC gene and CPS1 gene, 3 were novel: (c.176T>C (p.L59P)) in the OTC gene, c.2938G>A (p.G980S) and c.3734T>A (p.L1245H) in the CPS1 gene. There was a high mortality rate of 77.78% (7/9) for all the defects combined. An OTC-deficient male and a CPS1-deficient female survived from episodes of hyperammonemia. Although prompt recognition of UCD and the use of alternative pathway therapy in addition to provision of appropriate nutrition and dialysis improved survival, the overall outcomes for the neonatal-onset type are poor in China.

MeSH terms

  • Age of Onset
  • Carbamoyl-Phosphate Synthase (Ammonia) / genetics*
  • China
  • Exome Sequencing
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hyperammonemia / complications
  • Hyperammonemia / genetics*
  • Hyperammonemia / metabolism
  • Hyperammonemia / pathology
  • Infant, Newborn
  • Male
  • Metabolomics / methods
  • Mutation / genetics
  • Ornithine Carbamoyltransferase / genetics*
  • Ornithine Carbamoyltransferase Deficiency Disease / genetics
  • Ornithine Carbamoyltransferase Deficiency Disease / metabolism
  • Ornithine Carbamoyltransferase Deficiency Disease / pathology
  • Urea Cycle Disorders, Inborn / complications
  • Urea Cycle Disorders, Inborn / genetics*
  • Urea Cycle Disorders, Inborn / metabolism
  • Urea Cycle Disorders, Inborn / pathology

Substances

  • Ornithine Carbamoyltransferase
  • CPS1 protein, human
  • Carbamoyl-Phosphate Synthase (Ammonia)