Urea Cycle Defects

Clinical Features

Urea cycle defects (UCDs) are characterized by (1) hyperammonemia, (2) encephalopathy, and (3) respiratory alkalosis. Several clinical disorders have been described involving defective urea cycle enzymes: ornithine transcarbamolase deficiency (OMIM 311250), carbamoyl phosphate synthetase I deficiency (OMIM 237300), argininosuccinate synthetase deficiency (OMIM 215700), argininosuccinate lyase deficiency (OMIM 207900), and arginase deficiency (OMIM 207800). Another cause of hyperammonemia is N-acetlyglutamate synthase (NAGS) deficiency (OMIM 237310; (Bachmann et al. 1981. PubMedID: 7453791). N-acetylglutamate is an essential activating cofactor for Carbamoyl Phosphate Synthetase I (CPS1) and, therefore, clinical signs of CPS1 and NAGS deficiencies are indistinguishable. In general, two clinical presentations of UCDs are recognized: an acute neonatal hyperammonemia form and a delayed onset form (Haberle et al. 2003. PubMedID: 12754705). UCDs can present with hyperammonemia, leading to coma and death if untreated. A number of effective treatments for UCDs are available (Berry and Steiner. 2001. PubMedID:11148550. Ah Mew et al. 2014. PubMedID:24880889).

Prevention

Prompt recognition of a UCD and treatment with various medications, along with dietary therapy, effectively lowers plasma ammonia levels and results in lower morbidity/mortality rates (Enns et al. 2007. PubMedID: 17538087).

Drug Treatment

NAGS deficiency is the only urea cycle disorder in which urea cycle function may be restored through a pharmacological agent (Heibel et al. Human Genome Variation Society. 2011; hgvs.org). N-Carbamylglutamate therapy has shown to result in significant ammonia detoxification (Gebhardt et al. 2005. PubMedID: 15877213). This treatment, along with ammonia scavengers like phenylbutyrate and L-Citrulline or L-arginine (depending on the defect), promote optimal removal of ammonia and decrease risk of further complications (National Urea Cycle Disorders Foundation. 2013; nucdf.org). UCDs such as those caused by mutations in NAGS require rapid and vigorous treatment in order to normalize ammonia concentration as fast as possible to avoid high mortality and neurological complications, making an early, accurate diagnosis essential (Fillippi et al. 2010. PubMedID: 19887858).

Dietary Therapy

Diet is one of the mainstays of the treatment of patients with urea cycle disorders. Protein intake should be properly adjusted and essential amino acid supplements should be used when necessary. All patients should also have an emergency regimen developed to prevent decompensation during periods of metabolic distress, making awareness of the disorder key in avoiding morbidity/mortality (Leonard, J. 2001. PubMedID: 11148548). Avoidance of high protein diets, Valproic acid and prolonged fasting allow a patient to maintain a higher quality of life and ensuring a better chance of survival (Lanpher et al. 2003, PubMedID: 20301396; ncbi.nlm.nih.gov/books/NBK1217).

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Disclaimer

This article is a summary of information that has been reported in the biomedical research literature. It is not medical advice for patients. All disease treatments should be under the direction of a qualified healthcare provider.

Last Updated: 4/23/2018