Urea Cycle Disorders

ByMatt Demczko, MD, Mitochondrial Medicine, Children's Hospital of Philadelphia
Reviewed/Revised Mar 2024
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Urea cycle disorders are characterized by hyperammonemia under catabolic or protein-loading conditions.

There are many types of urea cycle and related disorders (see the table) as well as many other amino acid and organic acid metabolism disorders. See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism.

Primary urea cycle disorders (UCDs) include carbamoyl phosphate synthase (CPS) deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency (argininosuccinic aciduria), arginase deficiency (argininemia), and N-acetylglutamate synthetase (NAGS) deficiency. The more “proximal” the enzyme deficiency is, the more severe the hyperammonemia; thus, disease severity in descending order is NAGS deficiency, CPS deficiency, OTC deficiency, citrullinemia, argininosuccinic aciduria, and argininemia.

Inheritance for all UCDs is autosomal recessive, except for OTC deficiency, which is X-linked.


Symptoms and Signs of Urea Cycle Disorders

Clinical manifestations range from mild (eg, failure to thrive, intellectual disability, episodic hyperammonemia) to severe (eg, altered mental status, coma, death).

Manifestations in female carriers of OTC deficiency range from growth failure, developmental delay, psychiatric abnormalities, and episodic (especially postpartum) hyperammonemia to a phenotype similar to that of affected males (ie, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures, death).

Diagnosis of Urea Cycle Disorders

  • Serum amino acid profiles

Diagnosis of urea cycle disorders is based on amino acid profiles. For example, elevated ornithine indicates CPS deficiency or OTC deficiency, whereas elevated citrulline indicates citrullinemia. To distinguish between CPS deficiency and OTC deficiency, orotic acid measurement is helpful because accumulation of carbamoyl phosphate in OTC deficiency results in its alternative metabolism to orotic acid.

Genetic testing can confirm the diagnosis.

Treatment of Urea Cycle Disorders

  • Dietary protein restriction

  • Arginine or citrulline supplementation

  • Possible liver transplantation

Treatment of urea cycle disorders is dietary protein restriction that still provides adequate amino acids for growth, development, and normal protein turnover.

urea cycle intermediates to encourage the incorporation of more nitrogen moieties into urea cycle intermediates, each of which is readily excretable. Arginine is also a positive regulator of acetylglutamate synthesis. Studies suggest that oral citrulline is more effective than arginine in patients with OTC deficiency (1).

Additional treatment is with sodium benzoate, phenylbutyrate, or phenylacetate, which by conjugating glycine (sodium benzoate) and glutamine (phenylbutyrate and phenylacetate) provides a “nitrogen sink.”

Despite these therapeutic advances, many UCDs remain difficult to treat, and liver transplantation is eventually required for many patients. Timing of liver transplantation is critical. Optimally, the infant should grow to an age when transplantation is less risky (> 1 year), but it is important to not wait so long as to allow an intercurrent episode of hyperammonemia (often associated with illness) to cause irreparable harm to the central nervous system.

Treatment reference

  1. 1. Imbard A, Bouchereau J, Arnoux JB, et al. Citrulline in the management of patients with urea cycle disorders. Orphanet J Rare Dis. 2023;18(1):207. Published 2023 Jul 21. doi:10.1186/s13023-023-02800-8

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

  1. Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information

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