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Urea Cycle Disorders

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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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), and arginase deficiency (argininemia). In addition, N-acetylglutamate synthetase (NAGS) deficiency has been reported. 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.

Table
icon

Urea Cycle and Related Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Comments

Ornithine-transcarbamoylase (OTC) deficiency (311250*)

OTC

Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate

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: Hemodialysis for emergent hyperammonemic crisis, sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, low-protein diet supplemented with essential amino acid mixture and arginine, citrulline

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: Sodium benzoate and arginine

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 (603814*, 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: Arginine supplementation

Argininemia (107830*)

Arginase I

Biochemical profile: Elevated plasma arginine, diaminoaciduria (argininuria, lysinuria, cystinuria, ornithinuria), orotic aciduria, pyrimidinuria

Clinical features: Growth and developmental delay, anorexia, vomiting, seizures, spasticity, irritability, hyperactivity, protein intolerance, hyperammonemia

Treatment: Low-protein diet, benzoate, phenylacetate

Lysinuric protein intolerance (dibasic aminoaciduria II; 222700*)

Dibasic amino acid transporter

Biochemical profile: Elevated urine lysine, ornithine, and arginine

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: Elevated plasma ornithine and urine ornithine, lysine, and arginine; low plasma lysine, glutamic acid, and glutamine

Clinical features: Myopia, night blindness, blindness, progressive loss of peripheral vision, progressive gyrate atrophy of choroid and retina, mild proximal hypotonia, myopathy

Treatment: Pyridoxine, low-arginine diet, lysine and alpha-aminoisobutyrate to increase renal loss of ornithine; proline or creatine supplementation

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

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

  • 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

  • Dietary protein restriction

  • Arginine or citrulline supplementation

  • Sodium phenylbutyrate

  • 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.

Arginine has become a staple of treatment. It supplies adequate 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. Recent studies suggest that oral citrulline is more effective than arginine in patients with OTC deficiency.

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.

Drugs Mentioned In This Article

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R-GENE 10
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