AUTHOR INFORMATION

Section 1 of 11

Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, February 3 2006, VOLUME 7, Number 2

INTRODUCTION

Section 2 of 11

Background: Ornithine transcarbamylase (OTC) deficiency is the most common of the urea cycle disorders. The muted enzyme protein results in the impairment of 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. 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, generation of which is chiefly from 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 Image 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 as well. 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. As a pathway involved in nucleic acid biosynthesis, pyrimidine biosynthesis is regulated very tightly; 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:

• In the US: One of the most enigmatic aspects of this genetic disorder is the age of onset, which is often beyond the childhood years in otherwise normal individuals. The estimated incidence 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 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 any age up to 40-50 years and beyond.

Mortality/Morbidity: Morbidity and mortality are high, especially in 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.

• 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

Section 3 of 11

History:

• Clinical presentation is complex because male hemizygotes usually present in infancy, while female heterozygotes may be totally asymptomatic.



• On the other hand, hemizygous males may also present at any age without any precedent symptoms or effects, while heterozygous females may be severely affected in childhood.



• While many of the symptomatic females may present because of skewed distribution of the mutant gene in hepatocytes by lyonization, reasons for late-onset male presentations remain obscure, although some 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, a carrier female will be 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, are somewhat variable in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is 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 ensued.



• Pulmonary


• • Tachypnea or hyperpnea may be present.
  
  
  
  • Apnea and respiratory failure may occur in latter stages.
  
  
  
• Abdominal: Hepatomegaly may be present and is usually mild.



• Neurologic


• • Poor coordination
  
  
  
  • Dysdiadochokinesia
  
  
  
  • Hypotonia or hypertonia
  
  
  
  • Ataxia
  
  
  
  • Tremor
  
  
  
  • Seizures and hypothermia
  
  
  
  • Lethargy progressing to combativeness to obtundation to 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 is highly variable, and close to 100 different gene alterations have been described.



• 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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Arginase Deficiency
Argininosuccinate Lyase Deficiency
Carbamoyl Phosphate Synthetase Deficiency
Citrullinemia
Hyperammonemia
Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Hyperinsulinemia
Methylmalonic Acidemia
N-Acetylglutamate Synthetase Deficiency
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)
Sepsis

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

Section 5 of 11

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, though 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. Exceptions to this exist.



• Serum amino acid quantitation may show elevated ornithine, glutamine, alanine, and relatively low citrulline, but these changes are also 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 will run control assays of nonlabile hepatic enzymes, but this cannot substitute for proper sampling and handling.

TREATMENT

Section 6 of 11

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 upon muscle amino acids for energy.



• In the patient who is comatose with extremely high blood ammonia levels (in some cases exceeding 2000 mg/dL), rapid reduction can be achieved with hemodialysis.



• Administration of sodium benzoate, arginine, and sodium phenylacetate intravenously is important treatment; 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 also in a large facility setting with laboratory monitoring available.

Consultations:

• Medical geneticist



• Metabolic disease specialist



• Dietitian

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	Arginine (R-Gene 10) -- Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol arginine when cleaved by arginase. Pituitary stimulant for the release of human growth hormone (HGH). Often induces pronounced HGH levels in patients with intact pituitary function.
Pediatric Dose	Hyperammonemic crisis: 0.66 g/kg/dose IV infused over 24 h; dilute in 25-35 mL dextrose 10% Maintenance treatment in a stable child: (administer as the free base) 0.4-0.7 g/kg/d PO
Contraindications	Documented hypersensitivity
Interactions	Coadministration with amphotericin, triamterene, amiloride, or spironolactone may increase risk of hyperkalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Renal impairment; diagnostic aid not intended for therapeutic use; may cause nausea, vomiting, headache, hyperkalemia, hyperglycemia, or venous irritation during IV administration

Drug Name	Sodium phenylacetate and sodium benzoate (Ammonul) -- 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 - Safety for use during pregnancy has not been established.
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

Section 8 of 11

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 monitored closely.
  
  
  
  • 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 well, 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 mother is a carrier.
  
  
  
  • All female siblings of the obligate heterozygous maternal carrier are potential carriers, while 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.

TEST QUESTIONS

Section 9 of 11

CME Question 1: Which of the following is not true of the clinical presentation of neonatal ornithine transcarbamylase (OTC) deficiency?

A: Symptoms often begin in the neonatal period.
B: OTC deficiency is observed only in males.
C: Because the urea cycle is complete only in the liver, liver function studies should be abnormal.
D: Coma rapidly supervenes if appropriate steps are not taken.
E: All of the above

The correct answer is C: While it is true that the urea cycle is complete only in the hepatocyte, improperly processed ammonia is not hepatotoxic but is neurotoxic.

CME Question 2: Which of the following is true of the presumed heterozygous female, regarding ornithine transcarbamylase deficiency?

A: Carrier females always are developmentally slow.
B: Significant metabolic stress (eg, from illness) can cause hyperammonemia.
C: Seizures are common.
D: All male offspring will die.
E: None of the above

The correct answer is B: As a consequence of lyonization, some heterozygous females may possess less than 50% of the normal amount of active enzyme. Significant stress, which increases the ammonia load, can lead to accumulation and neurotoxic symptoms.

Pearl Question 1 (T/F): The mother of a diagnosed ornithine transcarbamylase (OTC) deficient male always is heterozygous for the mutated gene.

The correct answer is False: Incidence of spontaneous mutation is considerable at the OTC locus; therefore, it is possible for the mother of an affected male to be genetically unaffected. It is this factor that must be addressed in genetic counseling and pedigree evaluation.

Pearl Question 2 (T/F): Orotic aciduria is important to the diagnosis of ornithine transcarbamylase deficiency because increases in urinary excretion of orotate rarely are observed in healthy humans.

The correct answer is True: Excretion of excess orotic acid in urine implies markedly increased conversion of carbamoylphosphate to orotate, by means of carbamoyls phosphate synthetase (CPS) II, the cytosolic enzyme. This process can occur when CPS is leaked from the mitochondrion because its metabolism is blocked.

Pearl Question 3 (T/F): The role of supplemental citrulline in therapy for ornithine transcarbamylase (OTC) deficiency is to aid in the incorporation of waste nitrogen.

The correct answer is True: The incorporation of a second waste nitrogen molecule normally occurs in the formation of argininosuccinate from citrulline. Because OTC deficiency blocks formation of citrulline, dietary provision of this compound circumvents the block and facilitates the normal argininosuccinic acid synthase step.

Pearl Question 4 (T/F): Adult males need not be screened when evaluating the metabolic status of an ornithine transcarbamylase deficiency pedigree.

The correct answer is False: All first-degree female relatives of the proven obligate heterozygote mother should be considered for evaluation. Even adult males should be considered for screening in this manner because late-onset presentation can be devastating.

PICTURES

Section 10 of 11

Caption: Picture 1. Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; it is also at this step that N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS). Compound 2 is citrulline, 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.
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BIBLIOGRAPHY

Section 11 of 11

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