At a Glance

Cabamyolphosphate synthetase I deficiency (CPS1) is an inherited disorder of urea cycle metabolism. Urea cycle disorders are a collection of eight enzymes involved in waste nitrogen excretion as urea, including N-acetylgutamate synthase deficiency (NAGS), ornithine transcarbamylase deficiency (OTC), citrullinemia type 1 (CIT1), citrin deficiency (including citrullinemia type 2, CIT2), argininosuccinic acidemia (ASA), and argninase deficiency (ARG).

All enzyme deficiencies, except ARG, may present with acute hyperammonemia. CPS1 is the first step in urea cycle metabolism capturing the first mole of nitrogen into carbamoylphospate and has an essential cofactor, N-acyetylglutamate, which is produced by NAGS. CPS1 is inherited in an autosomal recessive manner. Autosomal recessive inheritance means the individual has inherited two abnormal copies of the CPS1 gene, each gene containing a mutation. Both parents of an individual with CPS1 are carriers and do not manifest any symptoms of disease.

Individuals with CPS1 deficiency exhibit symptoms similar to other urea cycle disorders with hyperammonemia. Infants may present in the first few days of life with hyperammonemia with increasing lethargy, poor feeding, vomiting or irritability, and tachypnea similar to sepsis. They may rapidly progress to respiratory alkalosis as ammonia increases with cerebral edema, seizures, loss of reflexes, hypothermia, apnea, and coma. Infantile or childhood presentations include vomiting, irritability, and failure to thrive often triggered by illnesses. Infections, surgery, or other stressors that create a catabolic state may trigger later onset forms in older children, adolescents, or adults. These later onset presentations are often due to partial enzyme deficiencies and may not lead to severe, permanent brain damage and developmental delays often seen in the early, more severe onset forms.

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Other disorders that may present with hyperammonemia include liver failure, drug toxicity, or inherited organic acidemia, such as propionic acidemia or methylmalonic acidemia, that also have severe metabolic acidosis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Hyperammoneima is seen in urea cycle disorders.

Urea cycle disorders, such as CPS1 deficiency, can be diagnosed by quantitative plasma amino acid analysis. Elevations of glutamine, as alanine and asparagine, may be seen while levels of citrulline and arginine are low.

Urine organic acids will be unremarkable with no elevation of orotic acid.

Ammonia should be closely followed, initially every 2-3 hours, until levels are controlled through medical management or hemodialysis.

Follow-up testing for the acutely ill patient in a hyperammonemic crisis requires serial monitoring of arterial ammonia, serum electrolytes, arterial blood gas, blood glucose, and other testing in an intensive care unit. A biochemical geneticist should be consulted for management and treatment. Ongoing follow-up testing will be determined upon the use of hemodialysis or intravenous infusion of nitrogen scavengers for alternate pathway removal of nitrogen such as sodium benzoate and sodium phenylacetatae (Ammonul®) and intravenous L-arginine.

Blood glucose levels should be monitored, as these patients require a high rate of intravenous dextrose and intralipids with protein restriction. Additional medical stressors, such as infection or dehydration, should be diagnosed and treated. (Table 1)

Table 1.
Plasma amino acids Plasma amino acids Urine Organic Acids
Elevated glutamine Low citrulline No orotic acid

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The cause of elevations of ammonia must be carefully considered, as false positive elevations are frequently seen. In addition, plasma ammonia must be immediately placed in ice after collection and then run as soon as possible or frozen within 15 minutes of blood draw.

Elevations of glutamine and alanine may be seen in other disorders with hyperammonemia. Other urea cycle disorders, including NAGS, OTC, CIT1, citrin deficiency manifesting as CIT2, and ASA, also have elevations of glutamine and alanine.

Citrulline will be low in NAGS and OTC deficiency. Arginine is low or normal in all urea cycle disorders, except ARG deficiency. Citrulline may be elevated over 1000 µM in CIT1 and CIT2, and moderately elevated in ASA deficiency.

Argininosuccinic acid is only detected in ASA deficiency and may often coelute with leucine or isoleucine, requiring special sample preparation for accurate determination of ASA anhydrides.

Milder or later-onset forms may only show abnormalities of ammonia or plasma amino acids during acute exacerbations.

What Lab Results Are Absolutely Confirmatory?

It is not possible to differentiate CPS1 from NAGS deficiency clinically or on biochemical testing, although CPS1 is much more common.

Confirmation of CPS1 should be performed through DNA sequencing of CPS1 or enzyme analysis. Sequencing will detect the majority of cases, although the incidence of large gene deletions or duplications is not yet known.

Clinical testing of enzyme activity can be done from a fresh frozen liver biopsy specimen when confirmation is not possible through DNA sequence analysis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Immediate and long-term testing and treatment is necessary to prevent morbidity and mortality in urea cycle disorders.

Confirmation of CPS1 is done through quantitative plasma amino acid analysis and urine organic acid analysis.

Follow-up long-term testing for the nonacutely ill patient should include ongoing clinical management with regular monitoring of plasma amino acids, venous ammonia, and other clinical parameters, including a complete blood count (CBC), electrolytes, renal function testing, calcium, phosphorus, magnesium, and markers for liver disease (e.g., apartate aminotransferase, alanine aminotransferase, total and direct bilirubin, albumin, prealbumin, and coagulation parameters), and urinalysis should be checked and followed.

Dietary protein is important to ensure adequate growth and development. Over-restriction of protein may lead to increased metabolic stress and trigger a catabolic event and hyperammonemia.

Multiple vitamin and mineral deficiencies should also be carefully monitored.

Carnitine deficiency may also be found occasionally, and plasma total and free carnitine levels should be checked.

Long-term monitoring and follow-up should include such tests, along with trace minerals, zinc and selenium, and vitamins.

Affected individuals should have emergency plans in place for rapid measurement of ammonia and electrolytes to immediately implement treatment. Repeat diagnostic studies should also be collected if the diagnosis is uncertain in milder disease forms.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Results of the plasma amino acids, urine amino acids, and urine organic acids can be affected by the patient’s fasting status. If nonfasting or if the patient is receiving intravenous parental nutrition, test results may be difficult to interpret.

Urine amino acids are not able to provide sensitive quantitation of amino acids for confirmation of diagnosis. Repeat analysis at a recurrent event may be helpful along with additional diagnostic testing looking for other causes of hyperammonemia.

Clinical interpretation of abnormalities of glutamine, alanine, citrulline, arginine, and other amino acids is essential. It is often not possible to determine the significance without clinical information and additional diagnostic testing.

Isolated elevations of glutamine may be seen in other urea cycle disorders, liver disease, or any cause of hyperammonemia. Low glutamine levels often reflect improper sample handling.

Elevations of alanine may be seen in acute illness, with elevations of lactic acid, or with prolonged fasting. If seen with an elevated proline level, there is a higher suspicion for a primary lactic acidosis, such as pyruvate dehydrogenase complex deficiency or mitochondrial disorders.