The urea cycle is a metabolic pathway primarily in the liver that converts ammonia (derived from protein metabolism) into urea, which can be safely excreted in urine. The urea cycle is also the sole source of the endogenous production of arginine, ornithine, and citrulline. Some parts of the urea cycle occur in the cell cytoplasm, and others occur in the mitochondria.

Defects in the urea cycle can be caused by partial or complete loss of function of enzymes in the pathway itself, or in the transport proteins that shuttle products of the cycle between the cytosol and the mitochondria. Defects in the urea cycle lead to an accumulation of ammonia as well as precursor metabolites in the body. In severe cases, symptoms typically appear within the first few days of life, as affected infants initially seem healthy but rapidly develop hyperammonemia, resulting in cerebral edema, lethargy, seizures, and potentially coma. Without prompt intervention, these episodes can be fatal or cause permanent neurological damage. Milder or partial deficiencies may remain undetected until later in childhood or adulthood, often triggered by catabolic stress such as illness or fasting. Over time, individuals with UCDs are at risk for recurrent hyperammonemic crises, developmental delays, cognitive impairment, and chronic complications affecting liver and kidney function. Advances in early diagnosis, dietary management, ammonia-scavenging drugs, and liver transplantation have improved survival and long-term outcomes, but morbidity remains significant, emphasizing the need for ongoing monitoring and management strategies, with a particular emphasis on dietary management.

Conditions included in this guideline are described ( TABLE #3, Genetic Basis of Urea Cycle Disorders and Related Disorders). UCDs may be diagnosed based on clinical/biochemical presentations, confirmatory testing following abnormal results on newborn screening, or genetic testing. Further information can be found at https://www.ncbi.nlm.nih.gov/books/NBK1217/

¹Condition abbreviations taken from NIH/NLM Newborn Screening Coding and Terminology Guide .

In the United States, the Department of Health and Human Services developed the Recommended Uniform Screening Panel (RUSP) to guide states in the determination of which disorders to include on their newborn screening panels. The RUSP includes citrullinemia type 1 (CIT-I) and argininosuccinic aciduria (ASA) as primary screening targets, which are detected by elevated concentrations of citrulline in CIT-1 and citrulline +/- argininosuccinic acid in ASA. Citrin deficiency (CIT-II), also known as citrullinemia type 2, and argininemia (ARG) are included as secondary targets. The tests included in the newborn screening panel vary by state.

Some states also include OTC deficiency (OTC) and/or CPS1 deficiency (CPS) in their newborn screening panels identified through secondary analyte patterns and abnormal metabolite ratios, although these two conditions are not currently included in the RUSP.

Further information can be found at https://www.newbornscreening.info/information/information-for-providers/disorders-fact-sheets-for-providers/ and https://babysfirsttest.org/

Some affected individuals are identified through abnormal newborn screening results, and confirmatory diagnosis is made following the algorithms provided by the American College of Medical Genetics and Genomics (ACMG), available here: https://www.ncbi.nlm.nih.gov/books/NBK55827/

Other affected individuals are identified clinically based on presentation, biochemical markers, family history, and molecular genetic test results. More information can be found at https://www.ncbi.nlm.nih.gov/books/NBK1217/

Urea cycle disorders are inherited in an autosomal recessive pattern with the exception of OTC deficiency, which is inherited in an X-linked pattern.

Urea cycle disorders, amino acid transporter deficiencies, and other disorders that present like UCDs, along with their causative genes and affected enzymes or transporters, are listed here: TABLE #3, Genetic Basis of Urea Cycle Disorders and Related Disorders