Urea cycle disorder is a rare genetic disorder in which there is a full or partial deficiency in the enzymes of the urea cycle, causing a defect in the metabolism of excess nitrogen, and leading to hyperammonemia. This article reviews the clinical presentation, diagnosis, treatment, and drug-disease state implications of urea cycle disorders.

INTRODUCTION

The urea cycle is the final pathway for the excretion of nitrogen waste in mammals.1 When protein and other nitrogen containing molecules are broken down, ammonia (NH3/NH4+) is produced. Ammonia must be removed from the body secondary to its potential for toxicity. Ammonia may be toxic even in small amounts. In mammals, ammonia toxicity is most commonly manifested via the central nervous system, causing neurologic symptoms of varying severity, although it may be toxic to many other organ systems as well.2,3 Ammonia is detoxified via the urea cycle. The urea cycle is expressed primarily in the periportal hepatocytes and partially in the small intestine and kidneys.4 When ammonia is produced, it is transported to the liver where it is converted to urea, which has low toxicity, and then excreted via the kidneys. The urea cycle is composed of five different enzymes and one cofactor.1,5 

The enzymes and cofactor of the urea cycle include: (Figure 1)6 

  • Carbamyl phosphate synthase I (CPSI)

  • Ornithine transcarbamylase (OTC)

  • Agininosuccinic acid synthetase (ASS)

  • Argininosuccinic acid lyase (ASL)

  • Arginase (ARG)

  • Co Factor: N-acetyl glutamate synthetase (NAGS)

Figure 1:

The Urea Cycle.

Figure 1:

The Urea Cycle.

A urea cycle disorder occurs when there is a full or partial deficiency in the enzymes of the urea cycle causing a defect in the metabolism of excess nitrogen leading to hyperammonemia. There is no effective secondary clearance system for ammonia. Urea cycle disorders are inherited. Deficiencies of CPSI, ASS, ASL, NAGS, and ARG are inherited in an autosomal recessive manner. OTC deficiency is inherited in an X-linked manner.5 The estimated international prevalence of urea cycle disorder is said to be between 1:8000 and 1:44,000 live births. It is hard to estimate what the true prevalence is because many patients go undiagnosed, particularly those with partial enzyme deficiencies. Some infants with urea cycle disorder will die prior to a definitive diagnosis being made.7 The prevalence of urea cycle disorder in the United States is estimated to be 1:8200.9 

CLINICAL PRESENTATION

The commonalty amongst all of the urea cycle disorders with the exception of arginase deficiency is hyperammonemia.3 The signs and symptoms of hyperammonemia differ according to whether it is classified as acute or chronic. Some of the signs and symptoms associated with acute hyperammonemia include lethargy, somnolence, coma, and multiorgan failure. Signs and symptoms of chronic hyperammonemia include headaches, confusion, lethargy, self-chosen vegetarian diet, failure to thrive, behavioral changes, and learning and cognitive deficits. Common symptoms amongst both acute and chronic hyperammonemia include lethargy, seizures, and psychiatric symptoms.8 

The clinical presentation of urea cycle disorders is dependent on which enzymes of the urea cycle are deficient. Patients may have total absence (severe) of enzyme activity or partial (mild) absence. The signs and symptoms of urea cycle disorders are primarily neurologic but other nonspecific symptoms may be present.4 Patients with a total absence of enzyme activity will present with symptoms within 1–5 days of birth. Infants with urea cycle disorder initially appear healthy and are born to term with no prenatal complications. However they rapidly deteriorate. Early symptoms include poor feeding, vomiting, lethargy, irritability, tachypnea, and somnolence.1,5 Other symptoms may include respiratory alkalosis, which can be used as a diagnostic clue, as well as neuromuscular irritability and stridor. They will then develop more obvious neurologic and autonomic problems such as change in tone, loss of normal reflexes, vasomotor instability, and apnea. Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem. Without treatment, death usually results. Those that survive are usually severely handicapped both physically and mentally.1,5 The differential diagnosis in neonatal patients is sepsis and respiratory distress. These diseases are often suspected in neonates over urea cycle disorder leading to a delay in the diagnosis.4 

In patients with mild or partial urea cycle disorder, an accumulation of ammonia is often triggered by illness or stress and may occur at any stage of life. Episodes may be delayed for months to years. The hyperammonemia is typically less severe and the symptoms are more subtle than what is seen in the neonate. Symptoms include loss of appetite, vomiting, lethargy, behavioral abnormalities, and sleep disorders.5 Patients who present with mild or partial urea cycle disorder, which most commonly includes teens and adults, may also experience psychiatric symptoms including episodic psychotic disorder, bipolar disorder, and/or major depression. In these patients who present with urea cycle disorder later in life there is often also a dietary history of protein aversion or self-selective vegetarianism.3 Patients with an ARG deficiency will often present after the neonatal period with spasticity in the legs and developmental delay. They seldom have symptomatic hyperammonemia.1 

DIAGNOSIS

A serum ammonia concentration should be done in patients who are symptomatic and is considered the single most important laboratory test to detect urea cycle disorders.4 A plasma ammonia concentration of 150 micromol/L or higher associated with a normal anion gap and a normal plasma glucose is a strong indication of a urea cycle disorder.5 

A plasma amino acid analysis may help to make a tentative diagnosis. When evaluating the plasma amino acids in newborns one must be cognizant of decreased hepatic development. As a result, the amino acid concentrations in a newborn may vary from what is seen in children and adults.5 The presence or lack of citrulline may help to differentiate between proximal and distal urea cycle deficits. In neonatal onset, citrulline is either absent or present in trace amounts in those with CPSI and OTC deficiency and in late onset UCD it is present in low to normal concentrations. There is a 10-fold increase in citrulline in ASS deficiency. In ASL deficiency there is a 2 to 5-fold increase. In partial enzyme deficiencies arginine may be normal. It may also be reduced in all deficiencies except ARG in which it is elevated 5 to 7 fold. Glutamine, alanine, and asparagine are often elevated. These amino acids each serve as storage forms of waste nitrogen.4,5 Urinary orotic acid excretion helps to distinguish CPSI and OTC deficiency. It is normal or low in CPSI deficiency and significantly elevated in OTC deficiency.

Enzyme activity testing can be used to confirm the diagnosis of all urea cycle disorders. The use of enzyme activity analysis to confirm urea cycle disorder has decreased secondary to the invasive sampling required for some of the deficiencies. CPSI, OTC, and NAGS deficiencies require a liver biopsy to determine enzyme activity. Enzyme activity of ASL and ARG can be determined through a measurement of red blood cells.4 Genetic testing can also be done for all urea cycle disorders which is primarily done by polymerase chain reaction (PCR) and direct sequencing of DNA samples. Many laboratories will offer mutation analysis for OTC deficiencies because it is the most common urea cycle disorder. Genetic testing for the other urea cycle disorders is mostly done in specialized institutions.4 

In addition to the analysis of ammonia concentration, plasma amino acids, urinary orotic acid, enzyme activity, and gene mutations, a family history should also be evaluated. A family history going back three generations should be obtained paying particular attention to children. Relevant findings in neurologic signs and symptoms should be noted.5 

TREATMENT

Aside from a liver transplant, there is no cure for urea cycle disorders. Patients with urea cycle disorders will require lifelong treatment. The exception to this is patients with mild forms of urea cycle disorder or those that receive a liver transplant.4 The treatment of urea cycle disorders can be categorized as acute and chronic management. During acute management the strategies for treatment include stopping any dietary protein and giving a high energy/caloric intake, reducing plasma ammonia concentration, and utilizing alternative pathways for nitrogen excretion.

Once hyperammonemia is suspected all dietary protein should be eliminated. Exogenous protein should not be eliminated longer than 24 to 48 hours. If exogenous protein is limited for a longer duration of time this may lead to deficiencies in amino acids which may lead to further endogenous protein catabolism. At that point amino acids should be reinstituted.4 Therefore, eliminating exogenous protein is not sufficient as the sole method for treating acute hyperammonemia. High energy intake is used to decrease endogenous protein catabolism and may be given either orally or intravenously but is best achieved with intravenous solutions consisting of 10% glucose. Higher concentrations of glucose may be needed and can be used concomitantly with insulin.1,4 When ammonia concentrations are above 500 umol/L it becomes essential to reduce the ammonia concentration as quickly as possible. The recommended methods are hemodialysis or hemofiltration.1 Once the plasma ammonia concentration drops below 200 umol/L, dialysis can often be discontinued.5 In addition, there are currently two compounds utilized to conjugate amino acids. As a result of conjugation, the amino acids are excreted from the body as a compound other than urea and this in turn decreases the load on the urea cycle. Sodium benzoate, which may be given orally or intravenously, was the first compound introduced. Sodium benzoate conjugates to glycine forming hippurate which is then rapidly excreted. Benzoate reduces nitrogen on a mole per mole basis.1 Subsequent to the development of sodium benzoate, phenylacetate and phenylbutyrate were developed. Because of the unpleasant clingy odor associated with phenylacetate, phenylbutyrate, which is administered orally, is used. Phenylbutyrate is oxidized in the liver to phenylacetate which conjugates to glutamine and forms phenylacetylglutamine. For every 1 mole of phenylbutyrate given 2 moles of nitrogen are excreted.1 Arginine may be used as a long-term alternative pathway therapy for nitrogen excretion in patients with ASS or ASL deficiencies at a dose of 500–700 mg/kg/day.10 

In chronic management of urea cycle disorders the strategies used are strict adherence to a low protein diet, replacing deficient nutrients, and utilizing alternative pathways of nitrogen excretion.1 Protein should be restricted to the minimum daily intake of natural protein. When restricting protein, it is important not to over-restrict which may cause malnutrition, essential amino acid deficiencies, and impaired growth. The amount of protein intake required should be reevaluated particularly during infancy and childhood when protein requirements may vary.4 Essential amino acid mixtures, dosed at 0.7 grams/kg/day, are used in patients with urea cycle disorders to avoid deficiencies. When restricting the diet, vitamin intake make also be decreased requiring vitamin supplementation as well.1,4 Once the acute hyperammonemia is controlled, patients will need to continue alternative pathway therapy to help continue metabolic control. The dose of alternative pathway pharmacologic agents during chronic management will vary according to the diet.1 

DRUG-DISEASE STATE IMPLICATIONS

Certain medications may be a trigger for hyperammonemic crisis in patients with urea cycle disorders, but the most common cause is valproic acid. Valproic acid is thought to deplete N-acetyle-glutamate (NAG). NAG is a cofactor for the production of carbomyl phosphate synthetase I (CPSI). This correlation lead the FDA in 2002 to add a contraindication to the package insert for valproic acid warning against the use of it in patients with known urea cycle disorders.11 When valproic acid is combined with other antiepileptic medications, particularly phenobarbital or phenytoin, the risk for hyperammonemia is well established. The mechanism for this reaction is not well understood but it is proposed that phenobarbital and/or phenytoin may increase the production of toxic valproic acid metabolite or they may have a synergistic effect on the urea cycle.11 

Other medications that have been associated with hyperammonemia in patients with urea cycle disorder include topiramate, carbamazepine, primidone, furosemide, hydrochlorothiazide, salicylates and high doses of chemotherapeutic agents, namely asparaginase and fluorouracil.7 

SUMMARY

Urea cycle disorder is a rare genetic disorder. Patients may have a total absence (severe) of enzyme activity or a partial (mild) absence. Severe urea cycle disorder is most commonly seen in the neonatal period and requires immediate attention, without which the prognosis is poor. Patients with mild forms of urea cycle disorder may not present with symptoms until later in life. Aside from a liver transplant there is no cure for urea cycle disorder. Treatment is aimed at maintaining metabolic control. This is achieved via acute and chronic therapeutic management. When treating a patient with urea cycle disorder one must be aware of the drug-disease state implications. Valproic acid is the most widely known agent to exacerbate urea cycle disorder and should preferably be avoided in these patients. Other factors that may trigger hyperammonemic crises include but are not limited to infections, fevers, vomiting, gastrointestinal or internal bleeding, fasting or starvation, large bolus doses of amino acids or proteins, psychological stress, surgery under general anesthesia, unusual protein load, and intravenous steroids.7 Urea cycle disorder may affect patients of all ages. However, there is paucity in the literature with regards to the implications of urea cycle disorder in adults. This may be because many patients with total absence of enzyme activity do not often live into adulthood. It may also be secondary to unrecognized symptoms as well as misdiagnosis that occurs in adult patients with partial absence of enzyme activity.

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