AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder. A mutant enzyme protein impairs the reaction that leads to condensation of carbamyl phosphate and ornithine to form citrulline. This impairment leads to reduced ammonia incorporation, which, in turn, causes symptomatic hyperammonemia (see Hyperammonemia). The gene for this enzyme is normally expressed in the liver and is intramitochondrial.

Pathophysiology

The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated by protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N-acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle.

Failure to incorporate carbamyl phosphate into citrulline by condensation with ornithine (see Media file 1) results in an excess of both substrates for the reaction. The consequent increase in hepatic ornithine is often reflected in an elevated serum level. By contrast, excessive mitochondrial carbamyl phosphate finds its way into the cytosol, where it functions as substrate for the carbamoyl phosphate synthetase (CPS) II reaction. This results in orotic acid, which is a normal intermediate in pyrimidine biosynthesis. Pyrimidine biosynthesis is regulated very tightly because it is a pathway involved in nucleic acid biosynthesis; thus, increases in urinary excretion of orotate are rarely observed in normal humans. Neither conversion of CPS to orotate nor hepatic leakage of ornithine can prevent the rapid development of hyperammonemia.

Frequency

United States

One of the most enigmatic aspects of this genetic disorder is the age of onset, which is often after childhood in otherwise normal individuals. The estimated incidence rate of 1:80,000 live births must be viewed with some degree of reservation because late-onset cases may go undetected. More recent estimates place the overall incidence rate of urea cycle defects in the range of 1:20,000, making ornithine transcarbamylase deficiency far more common than the previous estimate. As with the other urea cycle enzyme defects, clinical onset is often rapid and devastating in a patient who is genetically affected; however, in older individuals, the initial onset can occur at age 40-50 years or older.

Mortality/Morbidity

Morbidity and mortality are high, especially in patients with the neonatal form.

Sex

• As an X-linked trait, ornithine transcarbamylase deficiency is somewhat unusual among inherited biochemical disorders. Carried on the X chromosome, the mutant ornithine transcarbamylase gene regularly manifests in hemizygous males; although, as mentioned above, the age of clinical onset can be unpredictable.
• Based on reports in the literature, many heterozygous females are also seriously affected, occasionally suffering mental retardation and even death from hyperammonemia.
• The severity of disease in carrier females is conditioned by the nature of the mutation and the random inactivation of the mutant gene, according to the Lyon hypothesis.

CLINICAL

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History

• Clinical presentation is complex because male hemizygotes usually present in infancy, whereas female heterozygotes may be totally asymptomatic.
• On the other hand, hemizygous males may also present at any age without any precedent symptoms or effects, whereas heterozygous females may be severely affected in childhood.
• Although many symptomatic females may present because of skewed distribution of the mutant gene in hepatocytes due to lyonization, reasons for late-onset male presentations remain obscure; however, some males clearly have residual enzyme activity.
• Neonatal presentation is generally catastrophic.
• • The late-onset–affected male usually presents with no prior history consistent with hyperammonemia in childhood and suffers a rapid decompensation and demise, similar to the neonatal pattern.
  • More often, heterozygous females are asymptomatic or may experience a severe migrainelike headache in association with excessive protein intake.
  • Occasionally, carrier females are severely hyperammonemic in response to metabolic stress. This may accompany fasting or intercurrent illness, and the female may experience brain damage or death.
  • Varying levels of consciousness, pseudopsychotic episodes (eg, delusions), and persistent vomiting may herald clinical onset and should trigger a search for hyperammonemia, even in a previously asymptomatic adult of either sex.
• The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary somewhat in presentation, diagnostic features, and treatment. For these reasons, the urea cycle defects are considered individually in this journal; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of 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)
• 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.

Physical

• General
• • Signs of severe hyperammonemia may be present.
  • 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 the latter stages of disease progression.
• Abdominal: Hepatomegaly may be present and is usually mild.
• Neurologic
• • Poor coordination
  • Dysdiadochokinesia
  • Hypotonia or hypertonia
  • Ataxia
  • Tremor
  • Seizures and hypothermia
  • Lethargy that progresses to combativeness, obtundation, and coma
  • Decorticate or decerebrate posturing

Causes

• Ornithine transcarbamylase deficiency is an X-linked condition. The ornithine transcarbamylase gene is located on the X chromosome and has been mapped to band Xp21.1. It is approximately 73 kilobases in length, contains 10 exons and 9 introns, and is proximate to the gene for Duchenne muscular dystrophy.
• The nature of mutation in the ornithine transcarbamylase gene widely varies. As of 2006, 341 different gene alterations have been described; of those alterations, 149 are associated with neonatal-onset disease.¹ Seventy of the alterations were found in males with late-onset ornithine transcarbamylase deficiency.
• Affected family genetic evaluations have demonstrated a significant rate of spontaneous mutation.
• 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.

DIFFERENTIALS

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Other Problems to be Considered

Organic acid disorders (eg, isovaleric acidemia)
Lysinuric protein intolerance
Transient hyperammonemia of the newborn
Hepatic insufficiency/dysfunction
Mitochondrial diseases and pyruvate carboxylase deficiency
Valproate ingestion
L-asparaginase ingestion
Reye syndrome

WORKUP

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Lab Studies

• In a clinically affected individual, the sine qua non of diagnosis is demonstration of hyperammonemia.
• As in CPS deficiency, routinely obtained blood chemistries are not helpful, although a very low BUN level may present a diagnostic clue. This should not be interpreted as a substitute for blood ammonia studies because it is not sufficiently reliable.
• Liver and kidney function typically remain normal unless hypoxia or shock supervenes. However, exceptions have been noted.
• Serum amino acid quantitation may show elevated ornithine, glutamine, and alanine levels and relatively low citrulline levels, but these changes are neither invariable nor diagnostic. Urine organic acid and amino acid analysis are helpful in ruling out other conditions.
• Beyond demonstration of hyperammonemia, the only basis for clinical diagnosis is demonstration of elevated urinary orotic acid. This test also can be used, under appropriate conditions, to detect asymptomatic carriers.
• Remember that ornithine transcarbamylase is a mitochondrial hepatic enzyme and is subject to rapid postmortem degradation. Therefore, perform any liver biopsy prior to or immediately after death and properly handle the specimen in order to avoid artifactual diagnosis of deficiency. Experienced diagnostic laboratories perform control assays of nonlabile hepatic enzymes, but this cannot substitute for proper sampling and handling.

Other Tests

Enzymatic deficiency of the ornithine transcarbamylase enzyme can be further confirmed using molecular diagnosis. However, even using a combination of different molecular analytic strategies, only 80% of proven enzymatic deficiencies can be shown to have genetic mutation. The reasons for this inconsistency remain elusive. However, molecular techniques are very useful for prenatal diagnosis, especially when the specific mutation in the pedigree has been previously documented. 

TREATMENT

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Medical Care

• Immediate temporary discontinuation of protein intake in a symptomatic individual is mandatory, with compensatory increases in carbohydrates and lipids in order to offset any catabolic tendency to draw on muscle amino acids for energy.
• In a patient who is comatose with extremely high blood ammonia levels (in some cases exceeding 2000 mg/dL), rapid reduction can be achieved with hemodialysis.
• Intravenous administration of sodium benzoate, arginine, and sodium phenylacetate is important; however, only administer these drugs in a large medical facility setting with close laboratory monitoring available. Intravenous sodium benzoate and phenylacetate (Ammonul) was approved in the United States in February 2005.
• A biochemical geneticist and a highly trained nutritionist should administer long-term outpatient care in a large facility setting with laboratory monitoring available.

Consultations

• Medical geneticist
• Metabolic disease specialist
• Dietitian

Diet

Immediate temporary discontinuation of protein intake in a symptomatic individual is mandatory, with compensatory increases in carbohydrates and lipids in order to offset any catabolic tendency to draw on muscle amino acids for energy. A highly trained nutritionist should administer long-term outpatient care in a large facility setting with laboratory monitoring available. Scrupulous adherence to the dietary and medication recommendations is mandatory for survival.

MEDICATION

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Drug Category: Metabolic agents

These agents assist in the excretion of nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.

Drug Name	Sodium phenylacetate and sodium benzoate (Ammonul)
Description	Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mol is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for CPS, OTC, ASS, or ASL deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Adult Dose	Loading dose: 55 mL (5.5 g)/m2 IV over 90-120 min via central line Maintenance dose: 55 mL (5.5 g)/m2/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration
Pediatric Dose	Ammonul: <20 kg: Loading dose: 2.5 mL (250 mg)/kg IV over 90-120 min via central line Maintenance dose: 2.5 mL (250 mg)/kg/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration >20 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects of sodium benzoate/sodium phenylacetate; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate; corticosteroids may increase body protein metabolism, thereby increasing plasma ammonia levels; do not use concomitantly with oral sodium phenylbutyrate (Buphenyl) due to additive effects
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin binding sites on albumin); because of sodium content, exercise caution when giving to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance; IV must be diluted with dextrose 10% and administered via central line; phenylacetate may cause neurotoxicity; typically administered with antiemetic to prevent common occurrence of nausea and vomiting; caution in severe congestive heart failure or severe renal insufficiency since it contains large amount of sodium (30.5 mg/mL in undiluted IV product)

FOLLOW-UP

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Further Outpatient Care

• A biochemical geneticist must oversee patient care because the metabolic integrity of such an individual is very tenuously poised.
• Proper nutrition does not follow the usual nutritional rules, and any variations from what is appropriate may result in disaster. This is true throughout life but mostly in the growing infant and adolescent child in whom requirements may fluctuate weekly and must be closely monitored.
• Scrupulous adherence to the dietary and medication recommendations is mandatory for survival. Under no circumstances should this be undertaken by a general physician without close guidance from an expert in the care of patients with inherited metabolic diseases.

Prognosis

• Most affected male infants with neonatal presentation have not escaped the initial episode with normal mentation. Nonetheless, survival for many years can be achieved with very careful monitoring; use of oral citrulline, benzoate, and phenylacetate; and scrupulous dietary attention.
• Prognosis for older males with initial onset remains unclear because so many remain undiagnosed until very late in the clinical course.
• Most heterozygous females appear to be relatively healthy, except for a propensity to develop severe headaches with high protein intake. Women and children who are mildly affected can have an excellent prognosis with proper care.

Patient Education

• Family pedigree studies in this disease are essential for the following 2 reasons:
• • The X-linked nature of the mutation leads to a 1:2 chance of recurrence in any subsequent male conceptus if the mother is a carrier.
  • All female siblings of the obligate heterozygous maternal carrier are potential carriers, whereas male siblings may be at risk for late-onset presentation. The second reason is derived from the first.
• Another compelling issue in family counseling is the overwhelming sense of guilt with which the carrier mother must deal.
• Finally, repeatedly reinforce the parents in their abilities to perceive early signs of hyperammonemia and to take immediate steps to obtain medical care. Prenatal diagnosis is possible.

MISCELLANEOUS

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Medical/Legal Pitfalls

Late-onset ornithine transcarbamylase deficiency should be considered in adult males with evidence of acute hepatic encephalopathy. Failure to consider this diagnosis may adversely impact first-degree female relatives and their offspring who might otherwise have been tested and appropriately counseled.  

MULTIMEDIA

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Media file 1:  Compounds that comprise the urea cycle are sequentially numbered, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; during this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS). Compound 2 is citrulline, which is 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.
	View Full Size Image
Media type:  Graph

REFERENCES

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13. Hauser ER, Finkelstein JE, Valle D, Brusilow SW. Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med. Jun 7 1990;322(23):1641-5. [Medline].
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15. Legras A, Labarthe F, Maillot F, et al. Late diagnosis of ornithine transcarbamylase defect in three related femalepatients: polymorphic presentations. Crit Care Med. Jan 2002;30(1):241-4. [Medline].
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17. McCullough BA, Yudkoff M, Batshaw ML, et al. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. Aug 14 2000;93(4):313-9. [Medline].
18. Morioka D, Kasahara M, Takada Y, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl. Nov 2005;11(11):1332-42. [Medline].
19. Nicolaides P, Liebsch D, Dale N, et al. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. Jan 2002;86(1):54-6. [Medline].
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Article Last Updated: Aug 23, 2007