There are many types of urea cycle and related disorders (see the table Urea Cycle and Related Disorders 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... read more ) as well as many other amino acid and organic acid metabolism disorders Overview of Amino Acid and Organic Acid Metabolism Disorders The kidneys actively reabsorb significant amounts of amino acids. Defects of amino acid transport in the renal tubule include cystinuria and Hartnup disease, which are discussed elsewhere. Amino... read more . See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism Approach to the Patient With a Suspected Inherited Disorder of Metabolism Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .
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 Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , except for OTC deficiency, which is X-linked X-Linked Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more .
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 of urea cycle disorders is based on amino acid profiles Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more . 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 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.