Carbamoylphosphate Synthetase Deficiency

Background
Metabolism of amino acids generates ammonia, a highly toxic nitrogen-containing molecule that is eliminated from the body by its incorporation into urea, a non-toxic end product excreted through the kidneys. Carbamyl Phosphate Synthetase (CPS) catalyzes the first step in the detoxification of ammonia through formation of carbamyl phosphate, which enters the urea cycle and ultimately contributes its nitrogen to urea. Deficiency of CPS results in hyperammonemia and life-threatening symptoms. CPS is localized to the mitochondrial matrix and is present in high amount in liver and intestine. The CPS gene has been cloned and mutations identified in patients.

Clinical

Newborns with CPS deficiency appear normal for the first 24 hours. By 72 hours, symptoms of lethargy, vomiting, hypothermia, respiratory alkalosis and seizures progressing to coma appear. These patients are frequently thought to have sepsis. However, a key laboratory abnormality suggesting a urea cycle defect is low blood urea nitrogen, which should prompt measurement of ammonia. Patients who survive the newborn period often have recurrent episodes of hyperammonemia associated with viral infections or increased dietary protein intake. A neurologically damaged outcome is characteristic of CPS deficiency. Some patients have a later onset with a less severe course making diagnosis difficult.

Testing

Newborn screening by tandem mass spectrometry using a dried blood spot can detect elevated levels of glutamine and glutamate, together with low citrulline, suggesting CPS deficiency. Further testing is critical for the correct diagnosis. Plasma amino acids, urine organic acids and plasma acylcarnitine profiles will help distinguish CPS deficiency from other metabolic disorders exhibiting neonatal hyperammonemia. In contrast to several other urea cycle defects, patients with CPS deficiency do not excrete high levels of orotic acid. The activity of CPS can be measured in a liver biopsy. Mutation analysis of the CPS gene may be useful for prenatal diagnosis in future pregnancies.

Treatment

Treatment of acute hyperammonemia caused by CPS deficiency includes hemodialysis, peritoneal dialysis or arteriovenous hemofiltration. Several drugs conjugate major amino acids, forming metabolites that are excreted in the urine, which eliminates a major source of nitrogen from being converted to ammonia. Administration of sodium phenylbutyrate (or phenylacetate) conjugates glutamine, forming phenylacetylglutamine, which is excreted by the kidneys and removes waste nitrogen. In a similar fashion, citrulline is given to conjugate aspartic acid forming argininosuccinic acid. Administration of sodium benzoate results in conjugation of glycine, which is subsequently excreted in the urine. Patients who survive the initial presentation are placed on chronic treatment with phenylbutyrate, benzoate and supplemental arginine along with dietary protein restriction. Patients having onset in the newborn period face a poor outcome and significant risk of neurological damage or demise.

Because the diagnosis and therapy of CPS deficiency is complex, the pediatrician is strongly advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Inheritance

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

References

Brusilow, S.W. and Horwich, A. Urea Cycle Enzymes. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 85, pg. 1909-1963.

Caldovic L, Morizono H, Panglao MG, et al. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet 112:364-8, 2003.

Funghini S, Donati MA, Pasquini E, et al. Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Hum Mutat 22:340-341, 2003.

Maestri, N.E., Hauser, E.R., Bartholomew, D., et al. Prospective treatment of urea cycle disorders. J Pediatrics 119:923, 1992.

Rutledge, S.L., Havens, P.L., Haymond, M.W., et al. Neonatal hemodialysis: Effective therapy for the encephalopathy of inborn errors of metabolism. J Pediatrics 116:125, 1990.

Web Sites

SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites.

National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.

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