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.
Urea Cycle and Related Disorders
Disease (OMIM Number) | Defective Proteins or Enzymes | Comments |
|---|---|---|
Ornithine-transcarbamoylase (OTC) deficiency (311250*) | OTC | Biochemical profile: Clinical features: In males, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures, death In female carriers, variable manifestations, ranging from growth delay, small stature, protein aversion, and postpartum hyperammonemia to symptoms as severe as those in males with the deficiency Treatment: Experimental attempts at gene therapy, liver transplantation (which is curative) |
N-Acetylglutamate synthetase deficiency (237310*) | N-Acetylglutamate synthetase | Biochemical profile: Similar to OTC deficiency except for normal to low urine orotate Clinical features: Similar to OTC deficiency except carriers are asymptomatic Treatment: Similar to OTC deficiency but also N-carbamylglutamate supplementation |
Carbamoyl phosphate synthetase (CPS) deficiency (237300*) | Carbamoyl phosphate synthetase | Biochemical profile: Similar to OTC deficiency except for normal to low urine orotate Clinical features: Similar to OTC deficiency except carriers are asymptomatic Treatment: |
Citrullinemia type I (215700*) | Argininosuccinic acid synthetase | Biochemical profile: High plasma citrulline and glutamine, citrullinuria, orotic aciduria Clinical features: Episodic hyperammonemia, growth failure, protein aversion, lethargy, vomiting, coma, seizures, cerebral edema, developmental delay Treatment: Similar to that for OTC deficiency except citrulline supplementation is not recommended Liver transplantation |
Citrullinemia type II (605814*, 603471*) | Citrin | Biochemical profile: Elevated plasma citrulline, methionine, galactose, and bilirubin Clinical features: With neonatal onset, cholestasis resolved by 3 months With adult onset, enuresis, delayed menarche, sleep reversal, vomiting, delusions, hallucinations, psychosis, coma Treatment: Liver transplantation; otherwise no clear treatment |
Argininosuccinic aciduria (207900*) | Argininosuccinate lyase | Biochemical profile: Elevated plasma citrulline and glutamine, elevated urine argininosuccinate Clinical features: Episodic hyperammonemia, hepatic fibrosis, elevated liver enzymes, hepatomegaly, protein aversion, vomiting, seizures, intellectual disability, ataxia, lethargy, coma, trichorrhexis nodosa Treatment: |
Argininemia (107830*) | Arginase I | Biochemical profile: Clinical features: Growth and developmental delay, anorexia, vomiting, seizures, spasticity, irritability, hyperactivity, protein intolerance, hyperammonemia Treatment: Low-protein diet, benzoate, phenylacetate, liver transplantation |
Lysinuric protein intolerance (dibasic aminoaciduria II; 222700*) | Dibasic amino acid transporter | Biochemical profile: Clinical features: Protein intolerance, episodic hyperammonemia, growth and developmental delay, diarrhea, vomiting, hepatomegaly, cirrhosis, leucopenia, osteopenia, skeletal fragility, coma Treatment: Low-protein diet, citrulline |
Hyperornithinemia, hyperammonemia, and homocitrullinemia (238970*) | Mitochondrial ornithine translocase | Biochemical profile: Elevated plasma ornithine, homocitrullinemia Clinical features: Intellectual disability, progressive spastic paraparesis, episodic confusion, hyperammonemia, dyspraxia, seizures, vomiting, retinopathy, abnormal nerve conduction and evoked potentials, leukodystrophy Treatment: Lysine, ornithine, or citrulline supplementation |
Ornithinemia (258870*) | Ornithine aminotransferase | Biochemical profile: Clinical features: Myopia, night blindness, blindness, progressive loss of peripheral vision, progressive gyrate atrophy of choroid and retina, mild proximal hypotonia, myopathy Treatment: |
Hyperinsulinism-hyperammonemia syndrome (606762*) | Hyperactivity of glutamate dehydrogenase | Biochemical profile: Elevated urine alpha-ketoglutarate Clinical features: Seizures, recurrent hypoglycemia, hyperinsulinism, asymptomatic hyperammonemia Treatment: Prevention of hypoglycemia |
* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man (OMIM) database. | ||
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. 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.
Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information
