Urea cycle disorders

UCDs are a group of rare inborn metabolic errors caused by deficiencies in enzymes or transporters of the urea cycle, leading to the accumulation of ammonia and other toxic metabolites in the body. These disorders include deficenies of N-acetylglutamate synthase, carbamoylphosphate synthetase 1, ornithine transcarbamylase, arginosuccinate synthetase (citrullinemia type 1), argininosuccinate lyase (argininosuccinic aciduria), arginase, ornithine translocase (hyperornithinemia-hyperammonemia-homocitrullinuria syndrome), and citrin (citrullinemia type 2).

The urea cycle is the primary pathway for converting excess nitrogen, in the form of ammonia, into urea for excretion. Deficiencies in specific enzymes or transporters disrupt this cycle, leading to the accumulation of ammonia (with a normal anion gap and normal blood glucose) and other metabolites (such as glutamine, alanine, and asparagine). Hyperammonemia disrupts potassium homeostasis and water transport in the brain, resulting in cytotoxic cerebral edema.

The incidence of UCDs in the US is estimated at 1 per 35,000 births.

Complete enzyme or transporter deficiencies typically present with severe hyperammonemia within the first week of life, causing symptoms such as vomiting, poor feeding, lethargy, hypothermia, and coma. Partial deficiencies usually present later in life with milder symptoms, including protein aversion, food refusal, frequent vomiting, poor appetite, and adverse reactions to high-protein foods. Hyperammonemic episodes may be triggered by infections, high protein intake, certain drugs, or other stressors, leading to acute metabolic decompensation.

The prognosis of UCDs varies according to the specific disorder, the severity of enzyme deficiency, and the timing of diagnosis and intervention. Early detection through newborn screening and prompt management can improve outcomes and reduce the risk of severe neurological damage. Fatality during the first hyperammonemic episode in neonatal-onset UCDs has been reported at 27%, but it is declining with the widespread use of RRT.