AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 (H₂N-CO-PO₃₂-), in which the carbon atom is derived from bicarbonate. The process is exclusively mitochondrial and requires the expenditure of one ATP molecule.

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.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.²
• 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).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: 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.

Drug Name	Sodium phenylbutyrate (Buphenyl)
Description	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.
Pediatric Dose	0.5 g/kg/d PO divided tid pc
Contraindications	Documented hypersensitivity; severe hypertension; heart failure; renal dysfunction; acute hyperammonemia
Interactions	Valproate and haloperidol may increase ammonia levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Because of sodium content, avoid in patients with CHF, severe renal dysfunction, and sodium retention with edema

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

• Family counseling
  
  
  • 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• 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. 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].
3. 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].
4. 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].
5. Eather G, Coman D, Lander C, et al. Carbamyl phosphate synthase deficiency: diagnosed during pregnancy in a 41-year-old. J Clin Neurosci. 2006;13:702-706.
6. 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.
7. 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].
8. 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].
9. 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].
10. 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.
11. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S21-S29. [Medline].
12. 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].
13. 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.
14. 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].

Article Last Updated: Jun 13, 2007