eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Carbamoyl Phosphate Synthetase Deficiency

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

Updated: Mar 23, 2009

Introduction

Background

Carbamoyl phosphate synthetase (CPS) deficiency is a urea cycle defect that results from a deficiency in an enzyme that mediates the normal path for incorporation of ammonia. CPS is derived from catabolism of amino acids into a 1-carbon compound (H₂ N-CO-PO₃₂ -), in which the carbon atom is derived from bicarbonate. The process is exclusively mitochondrial and requires the expenditure of one ATP molecule.

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.

Pathophysiology

Two hepatocellular enzymes exist: CPS I and CPS II. CPS I is exclusively intramitochondrial, and its deficiency is responsible for the disease. CPS I is the most plentiful single protein in hepatic mitochondria, accounting for about 20% of the matrix protein. CPS II is exclusively cytosolic and is an important enzyme in de novo synthesis of pyrimidine nucleotides. The regulation of CPS I activity depends on the levels of N -acetylglutamate (see N-Acetylglutamate Synthetase (NAGS) Deficiency).

In patients with homozygous CPS I deficiency, the ability to fix waste nitrogen is completely absent, resulting in increasing levels of free ammonia with the attendant effects on the CNS. A recent molecular and functional examination of the mutational effects showed that, although some mutations affect both substrate affinity and efficiency of the reaction, others affect one more than the other.¹ Some mutations are associated with enhanced RNA instability, which leads to diminished protein synthesis.

The hepatic urea cycle is the major route for waste nitrogen disposal. Waste nitrogen is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and may result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator of CPS I, which initiates incorporation of ammonia into the cycle.

Frequency

United States

CPS deficiency is rare. As with all the urea cycle defects, as well as most of the inborn errors, citing incidence figures is impossible because new cases are generally diagnosed randomly without the benefit of population screening.

International

According a study of urea cycle diseases in Finland, 3 cases of CPS deficiency had been reported by 2007.²

Mortality/Morbidity

Mortality and morbidity rates are high. Untreated CPS deficiency is likely fatal.

Sex

CPS deficiency is autosomal recessive; thus, the incidence between the sexes is approximately equal.

Age

CPS deficiency has been reported in patients of all ages, from newborns to adults.

• In adults, some individuals remain unaffected until onset in early-to-mid adulthood, whereas others gradually sustain brain damage from infancy until diagnosis.
• In newborns, CPS deficiency is generally catastrophic in nature and leads to rapid demise without immediate recognition and treatment.

Clinical

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.³
• 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)

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

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).

Differential Diagnoses

Other Problems to Be Considered

Organic acid disorders (eg, isovaleric acidemia)
Lysinuric protein intolerance
Transient hyperammonemia of the newborn
Hepatic insufficiency or dysfunction
Mitochondrial diseases and pyruvate carboxylase deficiency
Valproate ingestion
L-asparaginase ingestion
Reye syndrome
Sepsis

Workup

Laboratory Studies

• Routine laboratory studies are of no diagnostic help. The clue to the presence of carbamoyl phosphate synthetase (CPS) deficiency may be a BUN level below the reference range. In contrast to older studies, this is merely a clue, is not always present, may occur in early fasting, and is quite unreliable. Nonetheless, when present, a BUN level below the reference range should trigger a search for hyperammonemia.
• Liver function is normal unless hypoxia has occurred in association with seizures. The same is true of renal function.
• The sole laboratory criterion for early diagnosis is a blood ammonia level. Obtain a blood level simultaneously with the usual laboratory workup as a part of the investigation of a critically ill neonate or infant. Determine blood ammonia level in adults with unexplained lethargy or coma.
  
  
  • Ammonia levels are usually 10-20 times higher than reference range.
  • Ammonia values greater than 1000 mg/dL are common. Blood amino acid changes are not specific to provide a diagnosis but are important in the differentiation of CPS deficiency from other urea cycle disorders.
• Urine orotic acid levels are within the reference range.
• Urine organic acid analysis is important to rule out organic acid disorders.
• Definitive testing requires liver biopsy and enzyme analysis.
• Postmortem findings are completely nonspecific, and, as a mitochondrial enzyme, CPS I is liable to rapid inactivation. Therefore, obtain hepatic samples for enzyme diagnosis during life, if possible, or immediately after death.

Imaging Studies

• A recent report suggests that single-voxel magnetic resonance spectroscopy permits the monitoring of brain glutamine and brain glutamate levels. This may be a more accurate means of monitoring the effects of an acute hyperammonemic episode on the brain than monitoring blood ammonia levels as treatment proceeds.

Other Tests

• Electroencephalography reveals nonspecific diffuse encephalopathy.
• Molecular genetic diagnosis may be available.

Procedures

• Approach lumbar puncture with great caution because of the potential for cerebral edema.

Treatment

Medical Care

• Depending on clinical status and the blood ammonia level, the logical first step is to reduce protein intake and to attempt to maintain energy intake. Initiate intravenous infusion of 10% glucose (or higher, if administered through a central line) and lipids.
• Intravenous sodium benzoate and sodium phenylacetate may be helpful. Arginine is usually administered with benzoate and phenylacetate. This is best administered in the setting of a major medical center, especially as this is an investigational new drug.
• In patients with an extremely high blood ammonia level, rapid treatment with hemodialysis is indicated.
• Metabolic disease specialists should provide long-term care with very close and frequent follow-up.

Consultations

• Medical geneticist
• Metabolic disease specialist
• Dietitian

Diet

• An appropriate diet must meet minimal protein requirements for growth and must include scrupulous monitoring.
• These requirements change with age, and caloric needs must also be met in order to appropriately use the requisite protein.

Medication

Endocrine and metabolic agents

The use of benzoate and phenylacetate is based on the need to provide alternate routes for waste nitrogen disposition. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl coenzyme A (CoA) and then conjugated with glutamine to form phenylacetylglutamine. Each of these 2 pathways results in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.

Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul)

Combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. The PO product (Ucephan) and IV product (Ammonul) contain a combination of sodium benzoate 10 g and sodium phenylacetate 10 g/100 mL (100 mg of each/mL).

Dosing

Adult

Pediatric

Ammonul 10% injection (100 mg/mL)
Loading dose: 250 mg (2.5 mL)/kg IV infused over 90 min via central line
Maintenance dose: 250 mg (2.5 mL)/kg IV infused over 24 h via central line
Dilute IV dose in 30 mL/kg of dextrose 10%
Ucephan oral
Oral maintenance dose: 375 mg/kg/d PO divided tid/qid in conjunction with a low-protein diet

Interactions

Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin-binding sites on albumin); because of sodium content, exercise caution when administering to patients with CHF, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbances; IV must be diluted with dextrose 10% and administered via a central line; phenylacetate may cause neurotoxicity; typically administered with antiemetic to prevent common occurrence of nausea and vomiting; caution in severe CHF or severe renal insufficiency because it contains a large amount of sodium (30.5 mg/mL in undiluted IV product)

Sodium phenylbutyrate (Buphenyl)

Prodrug rapidly converted orally to phenylacetylglutamine, which serves as substitute for urea and is excreted in the urine carrying 2 mol of nitrogen per mol of phenylacetylglutamine, assisting in clearance of nitrogenous waste.

Dosing

Adult

Pediatric

0.5 g/kg/d PO divided tid pc

Interactions

Valproate and haloperidol may increase ammonia levels

Contraindications

Documented hypersensitivity; severe hypertension; heart failure; renal dysfunction; acute hyperammonemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Because of sodium content, avoid in patients with CHF, severe renal dysfunction, and sodium retention with edema

Follow-up

Further Outpatient Care

• A biochemical geneticist or metabolic disease specialist should closely observe any patient with a diagnosed urea cycle defect, whether partial or complete. Oral sodium phenylbutyrate and arginine are often needed.
• A trained nutritionist should scrupulously monitor the diet of a patient with carbamoyl phosphate synthetase (CPS) deficiency.
• Periodic intellectual and neurologic evaluations are essential.

Prognosis

• A positive outcome is extremely unlikely in individuals with neonatal onset.
• Usually, the best prognosis is an infant who will be seriously impaired and will develop recurrent hyperammonemic episodes throughout infancy and childhood, sustaining further insults to the CNS.

Patient Education

• As an autosomal recessive trait, each parent is assumed to be an obligate heterozygote for CPS I deficiency. The likelihood of a recurrence is 25% (1:4) with each subsequent pregnancy, regardless of fetal sex.
• Prenatal diagnosis is theoretically available. If desired, contact the laboratory as early as possible.

Miscellaneous

Medicolegal Pitfalls

• Neonatologists or other medical caretakers must recognize the possibility of carbamoyl phosphate synthetase (CPS) I deficiency in a neonate with presumed sepsis.
• Untreated, the rate of decline is so rapid that antemortem diagnosis may not be made otherwise, and, because of the rapid deterioration of the enzyme postmortem, the diagnosis may be missed.

Multimedia

Media file 1: 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.

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

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

4. 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. Jun 10 1982;306(23):1387-92. [Medline].

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

6. 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.

7. 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.

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

9. 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].

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

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

12. 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.

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

14. 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].

15. 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.

16. 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. Sep 1992;86(3):275-9. [Medline].

Keywords

carbamoyl phosphate synthetase, carbamoyl phosphate synthetase deficiency, CPS, CPS deficiency, urea cycle defect, hyperammonemia, encephalopathy, respiratory alkalosis, carbamoyl phosphate synthetase I deficiency, CPS I, CPS II, hepatic urea cycle, urea production, pyrimidine nucleotide

Contributor Information and Disclosures

Author

Karl S Roth, MD, 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 Clinical 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, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
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, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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