Overview: What every practitioner needs to know

Are you sure your patient has a urea cycle defect (UCD)? What are the typical findings for this disease?

The urea cycle is made up by six enzymatic reactions that are responsible for the conversion of excess nitrogen into urea. Individual defects in five of these enzymes can lead to life threatening hyperammonemia, severe morbidity and death.

A complete defect of one of these enzymes typically leads to a severe neonatal presentation at 1-2 days of life, however a partial defect of one of these enzymes can present later in infancy, childhood, or even adulthood. It is an extremely important principle to remember that these disorders can present at any age. These enzymes of the urea cycle are N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase I (CPS-1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS, deficiency leading to Citrullinemia Type I ), and argininosuccinate lyase (ASA lyase).

Females with OTC deficiency (an X linked disorder) are variably affected based on X chromosome inactivation patterns. Their symptoms can range from asymptomatic to a full blown urea cycle defect.

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Arginase deficiency, a defect in the final step of the urea cycle, typically causes a picture of developmental delay and spastic diplegia (and not hyperammonemic crisis). Patients can also have seizures, ataxia, dystonia, or encephalopathy during the course of their disease.

A high index of suspicion is crucial for the treatment of these diseases, since they do not respond to “symptomatic” treatment.

Typical findings of a urea cycle defect (UCD) include nausea, vomiting, loss of consciousness and seizures. Ammonia will be elevated in all UCDs except arginase deficiency.


Nausea, vomiting, failure to thrive

Lethargy, coma, seizures

Respiratory failure

Transporter defects

Defects in transporters for intermediates of the urea cycle can also result in hyperammonemia, and characteristic plasma and urine amino acid profiles. These disorders include lysinuric protein intolerances (LPI), hyperornithinemia-hyperammonemia-homocitrullinemia syndrome (HHH syndrome), and citrullinemia type II (Citrin deficiency). See below for diagnostic laboratory patterns.

The importance of family history

Since OTC deficiency shows X-linked inheritance and the other urea cycle defects show autosomal recessive inheritance, a carefully taken family history can sometimes aid in diagnosis. It is important to ask about sibling history including prior neonatal or childhood deaths, peculiar eating habits (specifically protein avoidance), and cyclic vomiting, all of which could be a sign of an affected sibling. Maternal history is particularly important in the case of OTC deficiency, since females are variably affected based on patterns of X- inactivation. Maternal protein avoidance, cyclic vomiting, or developmental delay can all be signs of the mother being affected.

What other disease/condition shares some of these symptoms?

Defects in transporters carrying intermediates of the urea cycle can also lead to hyperammonemia. A defect in citrin, a mitochondrial aspartate transporter, can cause adult onset citrullinemia type II and hyperammonemia. In some cases, this is preceded earlier in life by infantile cholestasis. Liver transplant is the mainstay of treatment.

Defects of the mitochondrial ornithine transporter can lead to the hyperornithinemia-hyperammonemia-homocitrullinemia syndrome. This can be differentiated from other UCDs by the presence of homocitrulline in the urine amino acids and elevated ornithine on plasma amino acids.

Defects in the absorption of dibasic amino acids leads to lysinuric protein intolerance, and causes deficiencies of lysine, arginine, and ornithine. This can lead to hepatosplenomegaly, variable immunologic, renal, and pulmonary dysfunction, and episodes of hyperammonemia. Elevated urine and decreased plasma ornithine, arginine, and lysine can be detected on amino acid analysis.

Organic acidemias including methylmalonic acidemia and propionic acidemia can present with severe hyperammonemia due to secondary inhibition of the urea cycle. They can be differentiated from urea cycle defects by the presence of the offending organic acid on urine organic acid analysis. In addition, organic acidemias typically present with an anion gap metabolic acidosis, while urea cycle defects can present with a respiratory alkalosis due to ammonia stimulation of the medulla. However, this principle can be misleading, since later in decompensation in urea cycle defects there can be tissue stress and tissue death leading to a lactic acidosis and respiratory depression, or, less commonly, hyperammonemia in organic acidemias can cause a respiratory alkalosis.

Disorders of fatty acid oxidation can present with hypoketotic hypoglycemia and hyperammonemia. These disorders will have characteristic abnormal acylcarnitine and carnitine profiles.

What caused this disease to develop at this time?

Each defect of the urea cycle, with the exception of OTC deficiency, is caused by autosomal recessive inheritance. OTC deficiency is caused by X-linked recessive inheritance. Females with OTC deficiency are variably affected depending on the pattern of X chromosome inactivation.

Complete defects of one of these enzymes typically presents as a severe crisis in the newborn period with hyperammonemia, lethargy, coma and seizures. Partial defects, particularly in the case of OTC deficiency, can present later in life during times of catabolic stress, such as intercurrent illness or prolonged fasting. Crises subsequent to the original presentation typically are caused by periods of catabolic stress, as well.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

When a UCD is suspected a blood ammonia and blood gas should be sent. Hyperammonemia will be present, and a typical blood gas will show a respiratory alkalosis. However, this principle can be misleading, since this respiratory alkalosis is transient, and later in decompensation there can be a metabolic acidosis and respiratory depression.

Plasma chemistry panel should be sent to look for abnormalities in glucose, transaminases, urea (which will be low), and electrolytes.

Liver function tests and clotting studies should be sent since these can be abnormal.

Plasma acylcarnitine and carnitine profiles should be sent to rule out a fatty acid oxidation defect or an organic acidemia.

Plasma amino acids and urine organic acids can help to determine which specific enzyme is defective.

The urine organic acids in OTC deficiency, citrullinemia type I, and ASA lyase deficiency will have orotic acid. This is due to alternate conversion of excess carbamyl phosphate into orotic acid.

On plasma amino acids: OTC and CPS I deficiencies will cause increased glutamine and other “nitrogen sinks” such as alanine, and low citrulline and arginine; citrullinemia type I will cause elevated citrulline and low arginine; ASA lyase defciency will lead to elevated citrulline and argininosuccinic acid and low arginine. NAGS deficiency has elevated glutamine and alanine. Patients with arginase deficiency will have excess arginine.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not necessary to make a primary diagnosis of a urea cycle defect.

Imaging studies can be useful in the assessment of neurologic abnormalities associated with urea cycle defects.

Brain magnetic resonance imaging (MRI) of patients with a neonatal presentation can show diffuse cortical atrophy, basal ganglia lesions (specifically in OTC and CPS I deficiency), and occasionally cortical cystic malformations. Heterotopias and hypomyelination have also been observed in OTC deficient infants. Patients with later onset OTC deficiency, CPS-1 deficiency, citrullinemia type I and arginase deficiency can have findings on MRI including acute ischemia, dilated ventricles and abnormal myelination.

If you are able to confirm that the patient has a urea cycle defect, what treatment should be initiated?

Management of urea cycle defects should ideally involve a biochemical geneticist and nutritionist due to the complicated nature of the dietary and medical interventions.

Hyperammonemia leads to morbidity and mortality in urea cycle defects, and as such, reducing and maintaining ammonia at a physiologic level is crucial. Outcome is directly related to the amount of time a patient spends with an elevation of ammonia, as well as the level of the ammonia.

In symptomatic hyperammonemia, if the hyperammonemia cannot be rapidly controlled, hemodialysis or hemodiafiltration will be required. Protein should be restricted to reduce waste nitrogen. Intravenous glucose should be started to decrease catabolism. Intravenous sodium benzoate and sodium phenylacetate is administered to take advantage of alternative pathways of nitrogen excretion. L-arginine is given to replenish depleted urea cycle intermediates. Acute intercurrent hyperammonemia crises are treated similarly.

The majority of affected neonates will require hemodialysis or hemodiafiltration at initial presentation since other measures will not be effective in reducing the large ammonia load.

Long term treatment involves life long protein restriction and oral sodium benzoate and sodium phenylbutyrate. Arginine is also given to patients with citrullinemia type I, ASA lyase deficiency, and citrulline is given to patients with CPS-1 and OTC deficiency.

Arginase deficiency is treated with protein restriction.

Orthotopic liver transplant can be considered in severe defects.

What are the adverse effects associated with each treatment option?

Intravenous sodium phenylacetate/sodium benzoate has a side effects profile including cerebral edema, seizures, disseminated intravascular coagulation, metabolic acidosis, vomiting, hypokalemia, hyperglycemia among other effects. Careful monitoring, particularly during the first administration of this medication, is crucial.

What are the possible outcomes of a urea cycle defect?

Neurologic outcome is directly related to the amount of time that a patient spends hypermmonemic as well as the level of the hyperammonemia. If untreated, most infants will die from complications including pulmonary or cerebral hemorrhage. In extreme elevations in plasma ammonia there is an very high chance for irreversible neurologic damage or death, even if treated. It is important to consult a geneticist for help with family counseling in these situations.

In patients with a partial urea cycle defect, the hyperammonemia and thus the outcomes tend to be less severe. Many of these patients also are intellectually disabled, but not all are.

What causes this disease and how frequent is it?

OTC deficiency shows X-linked inheritance and the other urea cycle defects show autosomal recessive inheritance. Overall prevalence in the United States is estimated to be 1/8200.

How do these pathogens/genes/exposures cause the disease?

Defects in the urea cycle cause an inability to excrete waste nitrogen from protein metabolism in the form of urea. Waste nitrogen is therefore converted into ammonia which is neurotoxic and causes cerebral edema, among other harmful effects.

Other clinical manifestations that might help with diagnosis and management

ASA lyase deficiency can also present with hepatomegaly and chronic ataxia as part of the clinical picture. In addition, these patients can also have brittle hair (trichorrhexis nodosa).

What complications might you expect from the disease or treatment of the disease?

Patients with UCDs have episodes of hypermmonemic crises which are often not predictable, and every crisis is a metabolic emergency. Every hyperammonemic episode has the potential to have negative neurologic consequences. As a general principle, the more severe the enzymatic defect, the more difficult it will be to control and the more crises will occur.

Are additional laboratory studies available; even some that are not widely available?

DNA diagnosis is available and can be used for carrier detection and prenatal diagnosis in future pregnancies.

Liver tissue can also be used to diagnose the enzymatic defect in each UCD. Fibroblasts can be used to diagnose the enzymatic defect in citrullinemia type I and in ASA lyase deficiency. Red blood cells can be used to make an enzymatic diagnosis in ASA lyase and arginase deficiencies. In NAGS deficiency, a molecular diagnosis is preferred.

How can urea cycle defects be prevented?

Genetic counseling is very important in families affected by a UCD. In the autosomal recessive UCDs, there is a 25% chance that each subsequent child will be affected, a 50% chance that each subsequent child will be an unaffected carrier, and a 25% chance that each subsequent child will neither be affected nor be a carrier. In OTC deficiency, there is a 50% chance that each male child will be affected, and a 50% chance that a female child will be variably affected.

Intercurrent hyperammonemic crises are often difficult to anticipate or control, but prompt medical management during times of intercurrent illness is crucial for optimal outcome.

What is the evidence?

Bachmann, C. “Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation”. Eur J pediatr. vol. 162. 2003. pp. 410-416. (This paper discusses neurocognitive outcome in differently treated patients with urea cycle disorders. The authors conclude that protein restriction plus extensive nutritional treatment [arginine/citrulline, essential amino acid supplements] and sodium benzoate offers better survival than conservative management using only protein-restriction, but not necessarily improved cognitive outcome in survivors.)

Braissant, O. “Current concepts in the pathogenesis of urea cycle disorders”. Mol genet and metab. vol. 100. 2010. pp. S3-12. (This paper contains an extensive discussion of the central nervous system pathophysiology in urea cycle disorders. The authors conclude that the effects of ammonium on CNS may ultimately cause energy deficits, oxidative stress and cell death.)

Endo, F, Matsuura, T, Yanagita, K, Matsuda, I. “Clinical manifestations of inborn errors of the urea cycle and related metabolic disorders during childhood”. J Nutr. vol. 134. 2004. pp. 1605s-1609s. (A review of the clinical features associated with urea cycle defects and other disorders such as organic acidemias. Treatment principles are also discussed.)

Leonard, J, Fernandes, Saudubray, van den Berghe, Walter. “Chapter 20: Disorders of the urea cycle and related enzymes (2006)”. Inborn Metabolic Diseases. pp. 245-263. (An overview of principles of urea cycle disorders, pathways, and general treatment principles.)

Horwich, A, Brusilow, S, Scriver, C, Beaudet, A, Sly, W, Valle, D, Childs, B, Kinzler, K, Vogelstein, B. “Chapter 85: Urea cycle enzymes (2001)”. The metabolic and Molecular basis of Inherited Disease. (This is a seminal review of the history, molecular genetics, pathophysiology, and treatment of urea cycle disorders.)