Neonatal carbamoyl phosphate synthetase I deficiency with severe hyperammonemic coma: the first report from Palestine

Carbamoyl phosphate synthetase I deficiency (CPS1D) is the most proximal and severe urea cycle disorder, often presenting in the neonatal period with rapidly progressive hyperammonemia. Early symptoms are often nonspecific, posing significant diagnostic challenges and contributing to delays in targeted management. We report a term female neonate (37 + 6 weeks, 2600 g) who initially presented with transient tachypnea of the newborn and was managed with continuous positive airway pressure. At 36 h of life, she developed sudden desaturation and bradycardia requiring emergent intubation, and laboratory evaluation revealed severe hyperammonemia. Plasma amino acid analysis demonstrated markedly elevated glutamine and alanine with severely reduced citrulline, and urine organic acid analysis revealed undetectable orotic acid—a biochemical profile consistent with a proximal urea cycle defect. Despite immediate initiation of intravenous sodium benzoate and arginine at guideline-recommended doses, serum ammonia escalated to a peak of approximately 3300 µmol/L. Peritoneal dialysis was initiated as the sole available extracorporeal modality, given the absence of neonatal hemodialysis capacity within the regional healthcare network, and achieved a gradual biochemical reduction; however, no neurological recovery occurred. Whole-exome sequencing identified a previously unreported homozygous likely pathogenic CPS1D variant (NM_001875.5:c.4172 C > A; p.Thr1391Lys). The patient progressed to multiorgan failure and died on day six of life. This case illustrates the fulminant course of neonatal-onset CPS1D and the diagnostic difficulty posed by an initial nonspecific respiratory presentation. Notably, despite early ammonia detection and prompt initiation of guideline-directed management, the outcome was fatal—reflecting the intrinsic biological severity of the disorder and the absence of access to high-efficiency extracorporeal clearance and liver transplantation rather than a failure of timely recognition alone. A high index of suspicion for urea cycle disorders in neonates with unexplained encephalopathy or sudden decompensation, early metabolic evaluation, and rapid genomic testing remain essential components of management, even where definitive therapeutic options are limited. To our knowledge, this is the first report of CPS1D from Palestine, and it expands the global mutational spectrum by identifying a previously unreported homozygous CPS1 variant via whole-exome sequencing.