Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Carbamoyl Phosphate Synthetase Deficiency Clinical Presentation

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Aug 24, 2015
 

History

In homozygous neonates, early-onset lethargy and, in some cases, seizures are often the first signs of abnormality. Because the fetus is generally anabolic and maternal metabolism can usually manage the additional ammonia load from the fetus, intrauterine development is completely unaffected. Therefore, infants are usually born at term following a completely uneventful pregnancy and delivery.

Ammonia levels begin to rise after the maternal-fetal circulation is interrupted at birth, with a brief period of fasting. The baby becomes irritable, then lethargic, and, if untreated, comatose. Without rapid recognition and aggressive treatment, the infant suffers devastating CNS damage, coma, and death.

Some individuals with carbamoyl phosphate synthetase (CPS) deficiency reach adulthood prior to diagnosis. One known case involved a college-educated homozygous woman whose clinical onset occurred within hours after childbirth and resulted in death.[5]

The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in manifestation, diagnostic features, and management. For these reasons, the urea cycle defects are considered individually in this article; however, hyperammonemia is the common denominator and generally manifests clinically as a common constellation of signs and symptoms. As a consequence, the most striking clinical findings of each individual urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events. Symptoms include the following:

  • Anorexia
  • Irritability
  • Heavy or rapid breathing
  • Lethargy
  • Vomiting
  • Disorientation
  • Somnolence
  • Asterixis (rare)
  • Combativeness
  • Obtundation
  • Coma
  • Cerebral edema
  • Death (if treatment is not forthcoming or effective)
Next

Physical

General

Signs of severe hyperammonemia may be present (see Hyperammonemia).

Poor growth may be evident.

Head, ears, eyes, nose, and throat (HEENT)

Papilledema may be present if cerebral edema and increased intracranial pressure have occurred.

Pulmonary

See the list below:

  • Tachypnea or hyperpnea may be present.
  • Apnea and respiratory failure may occur in later stages.

Abdominal

Hepatomegaly may be present and is usually mild.

Neurologic

See the list below:

  • Poor coordination
  • Dysdiadochokinesia
  • Hypotonia or hypertonia
  • Ataxia
  • Tremor
  • Seizures and hypothermia
  • Lethargy progressing to combativeness, obtundation, and coma
  • Decorticate or decerebrate posturing
Previous
Next

Causes

CPS I deficiency is autosomal recessive. The structural gene for the enzyme is assigned to chromosome 2 and mapped to band 2q35. It has been sequenced and cloned.

Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms (see Arginase Deficiency).

Previous
 
 
Contributor Information and Disclosures
Author

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

References
  1. Yefimenko I, Frequet V, Marco-Marin C, et al. Understanding carbomyl phosphate synthetase deficiency: impact of clinical mutations on enzyme functionality. J Mol Biol. 2005. 349:127-141.

  2. Diez-Fernandez C, Hu L, cervera J, et al. Understanding carbomyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: effects of CPS1 mutations that concentrate in a central domain of unknown function. Mol Genet Metab. June 2014. 112:123-132. [Medline].

  3. Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. 2008 Oct. 97(10):1412-9. [Medline].

  4. Funghini S, Thusberg J, Spada M, Gasperini S, Parini R, Ventura L, et al. Carbamoyl phosphate synthetase 1 deficiency in Italy: clinical and genetic findings in a heterogeneous cohort. Gene. 2012 Feb 10. 493(2):228-34. [Medline].

  5. Wong LJ, Craigen WJ, O'Brien WE. Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann Intern Med. 1994 Feb 1. 120(3):216-7. [Medline].

  6. Gunz AC, Choong K, Potter M, et al. Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects. Int Med Case Rep J. August 2013. 6:41-48. [Medline].

  7. Häberle J, Shchelochkov OA, Wang J, Katsonis P, Hall L, Reiss S, et al. Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations. Hum Mutat. 2011 Jun. 32(6):579-89. [Medline].

  8. Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2012 Sep 7. [Medline]. [Full Text].

  9. Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, et al. Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate. J Pediatr. 2013 Jan 13. [Medline].

  10. Batshaw ML, Brusilow S, Waber L, Blom W, et al. Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Med. 1982 Jun 10. 306(23):1387-92. [Medline].

  11. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. 2001 Jan. 138(1 Suppl):S56-60; discussion S60-1. [Medline].

  12. Eather G, Coman D, Lander C, et al. Carbamyl phosphate synthase deficiency: diagnosed during pregnancy in a 41-year-old. J Clin Neurosci. 2006. 13:702-6.

  13. Eeds AM, Hall LD, Yadav M, et al. The frequent observation of evidence for nonsense-mediated decay in RNA from patients with caramyl phosphate synthetase I deficiency. Mol Genet Metab. 2006. 89:80-86.

  14. Farriaux JP, Ponte C, Pollitt RJ, Lequien P, et al. Carbamyl-phosphate-synthetase deficiency with neonatal onset of symptoms. Acta Paediatr Scand. 1977 Jul. 66(4):529-34. [Medline].

  15. Finckh U, Kohlschutter A, Schafer H, Sperhake K, et al. Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat. 1998. 12(3):206-11. [Medline].

  16. Freeman JM, Nicholson JF, Schimke RT, Rowland LP, et al. Congenital hyperammonemia. Association with hyperglycinemia and decreased levels of carbamyl phosphate synthetase. Arch Neurol. 1970 Nov. 23(5):430-7. [Medline].

  17. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007 Nov. 30(6):865-79. [Medline].

  18. Kojic J, Robertson PL, Quint DJ. Brain glutamine by MRS in a patient with urea cycle disorder and coma. Pediatr Neurol. 2005. 32:143-146.

  19. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. 2001 Jan. 138(1 Pt 2):S21-S29.

  20. Summar ML. Molecular genetic research into carbamoyl-phosphate synthase I: molecular defects and linkage markers. J Inherit Metab Dis. 1998. 21 Suppl 1:30-9. [Medline].

  21. Summar ML, Hall L, Christman B. Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab. 2004. 81Supplement 1:S12-S19.

  22. Verbiest HB, Straver JS, Colombo JP, van der Vijver JC, et al. Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma. Acta Neurol Scand. 1992 Sep. 86(3):275-9. [Medline].

 
Previous
Next
 
Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.