Urea Cycle Disorders

Urea Cycle Disorders result from mutations in genes encoding any of the eight enzymes or transporter proteins in the urea cycle: carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), carbamoyl phosphate synthetase 2 (CPS2), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginanase (ARG1), and the mitochondrial ornithine transporter 1 (ORNT1). Each enzyme catalyzes sequential steps in the conversion of ammonia and CO2 to urea. Enzyme deficiency prevents ammonia disposal, leading to hyperammonemia with toxic effects on the CNS. Neonatal-onset UCDs present in the first few days to weeks of life with poor feeding, vomiting, lethargy, and rapid progression to coma, seizures, and potentially death if untreated. Late-onset forms manifest with intermittent hyperammonemic crises triggered by infections, surgery, stress, or dietary protein intake. Symptoms include confusion, behavioral changes, ataxia, seizures, and encephalopathy. Chronic manifestations include developmental delay, intellectual disability, behavioral problems, and attention deficit. Chronic hyperammonemia even at modest elevations can impair cognitive function and development. Treatment involves ammonia-lowering medications (sodium phenylbutyrate, glycerol phenylbutyrate), protein restriction, supplementation with ammonia-scavenging amino acids, and management of precipitating factors.