At a Glance

Ornithine transcarbamylase deficiency (also known as OTC) 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-acetylglutamate synthase deficiency (NAGS), carbamyol phosphate synthetase I deficiency (CPS1), citrullinemia type 1 (CIT1), citrin deficiency (including citrullinemia type 2; CIT2), argininosuccinic acidemia (ASA), and arginase deficiency (ARG). All enzyme deficiencies, except ARG, may present with acute hyperammonemia.

OTC is the most common disorder of urea cycle metabolism. Patients with OTC cannot convert carbamoyl phosphate and ornithine into citrulline in the urea cycle.

OTC is inherited in an X-lined recessive manner, and males who inherit a single mutation in their OTC gene on the X-chromosome are the most commonly affected. Females may inherit single mutation in OTC on one of their two OTC genes. A carrier female is estimated to have at least a 15% chance of being affected with clinical symptoms and be at risk for hyperammonemia. Carrier (or heterozygote) females will have a 50% chance of transmitting this mutation to each son who would be clinically affected and a 50% chance of transmitting this mutation to each daughter who would also have a 15% chance of clinical disease.

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Individuals with OTC deficiency will exhibit symptoms similar to other urea cycle disorders with hyperammonemia. Infants are typically male and 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. Male and female infant or childhood presentations have been reported with 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.

Classical OTC will present in the newborn males with severe hyperammonemia. Milder cases of OTC in males have also been reported with onset of symptoms during childhood through adult years. These later-onset forms may only show abnormalities of ammonia or plasma amino acids during acute exacerbations.

Although OTC is X-linked disorder, at least 15% of heterozygote females manifest symptoms. Although symptoms may appear in infancy or early childhood, many girls only have a history of preferring to avoid eating meat or will be vegetarians.

Manifesting heterozygous OTC females are more frequently identified (than was previously estimated) and present with severe hyperammonemia, requiring the same degree of treatment as affected males. Not until they first develop hyperammonemia following a significant illness or surgery are they diagnosed, although diagnosis is often delayed because of failure to recognize the clinical symptoms, clinical history, or measure ammonia. Following this initial presentation, they typically have recurrent episodes of hyperammonemia and require dietary and medical treatment. Abnormalities of ammonia or plasma amino acids may only be detectable during acute exacerbations.

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?

Hyperammonemia is seen in urea cycle disorders.

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

Urine organic acids demonstrate a large elevation of orotic acid with levels greater than 20 µM being highly suspicious for OTC.

Ammonia should be closely followed initially every 2-3 hours until levels are controlled through medical management or hemodialysis. (Table 1)

Table 1.
Plasma amino acids Urine organic acids
Elevated GlutamineDecreased or absent Citrulline
Elevated orotic acid

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 is determined on the use of hemodialysis or intravenous infusion of nitrogen scavengers for alternate pathway removal of nitrogen, such as sodium benzoate and sodium phenylacetate (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.

Allopurinol loading tests have been used to screen for elevations of urinary orotate in individuals with suspected OTC deficiency. If the elevation of orotic acid is sufficient, this may help confirm diagnosis, but a negative test does not definitively rule out disease in males or carrier status in heterozygote females.

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, CPS1, CIT1, citrin deficiency manifesting as CIT2, and ASA, also have elevations of glutamine and alanine.

Citrulline will be low in NAGS and CPS1 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, as well as 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?

Although clinical history along with elevations of orotic acid and glutamine and very low or absent citrulline levels are often sufficient for diagnosis, confirmation of OTC should be performed through DNA sequencing of OTC or enzyme analysis.

Sequencing of OTC will only detect approximately 80% of mutations, whereas large gene deletions or duplications may detect another 10% of mutations. About 10% of all cases cannot currently be confirmed through DNA sequencing.

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 OTC is done through quantitative plasma amino acid analysis and urine organic acid analysis.

Follow-up, long-term testing for the non-acutely 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., aspartate 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 non-fasting 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.