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Carbamoyl Phosphate Synthetase Deficiency
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).
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References
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.
Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. Oct 2008;97(10):1412-9. [Medline].
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].
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].
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].
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.
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.
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].
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].
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].
Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. Nov 2007;30(6):865-79. [Medline].
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.
Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S21-S29. [Medline].
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].
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.
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].
Further Reading
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
