Practice Essentials
Ornithine transcarbamylase (OTC) deficiency is an X-linked genetic disorder of the urea cycle that leads to elevated levels of ammonia in the blood. One of the most enigmatic aspects of OTC is the age of onset, which is often after childhood in otherwise normal individuals.
See the image below.
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.
Signs and symptoms
Hyperammonemia from OTC deficiency can be manifested clinically by some or all of the following:
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Anorexia
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Irritability
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Heavy or rapid breathing
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Lethargy
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Vomiting
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Disorientation
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Somnolence
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Asterixis (rare)
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Combativeness
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Obtundation
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Coma [2]
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Cerebral edema
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Death (if treatment is not forthcoming or effective)
Presentation in males may be as follows:
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Male hemizygotes usually present in infancy
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Neonatal presentation is generally catastrophic
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Presentation may occur at any age, without any precedent symptoms or effects
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Late onset may involve rapid decompensation and demise, similar to the neonatal pattern
Presentation in female carriers may be as follows:
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More often, heterozygous females are asymptomatic
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Severe involvement may occur in childhood
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Heterozygous females may experience a severe migraine-like headache after excessive protein intake [3]
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Occasionally, metabolic stress (eg, from fasting or intercurrent illness) may result in severe hyperammonemia with brain damage or death
Physical findings may include the following:
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Poor growth
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Papilledema, in patients with cerebral edema and increased intracranial pressure
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Tachypnea or hyperpnea
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Apnea and respiratory failure, in the latter stages of disease progression
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Hepatomegaly, usually mild
Neurologic findings include the following:
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Poor coordination
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Dysdiadochokinesia
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Hypotonia or hypertonia
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Ataxia
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Tremor
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Seizures and hypothermia
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Lethargy that progresses to combativeness, obtundation, and coma
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Decorticate or decerebrate posturing
See Clinical Presentation for more detail.
Diagnosis
Demonstration of hyperammonemia is the sine qua non of diagnosis of OTC deficiency. At the extreme, serum ammonia levels may exceed 2000 mg/dL. Other possible findings on laboratory studies are as follows:
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Very low blood urea nitrogen (BUN) level
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Normal liver and kidney function in most cases, unless hypoxia or shock supervenes
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Elevated ornithine, glutamine, and alanine levels and relatively low citrulline levels
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Elevated urinary orotic acid level (may also detect asymptomatic carriers)
See Workup for more detail.
Management
Treatment of symptomatic OTC deficiency consists of the following:
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Immediate temporary discontinuation of protein intake
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Compensatory increases in dietary carbohydrates and lipids
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Hemodialysis for comatose patients with extremely high blood ammonia levels; rapid reduction can be achieved with hemodialysis
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Intravenous administration of sodium benzoate, arginine, and sodium phenylacetate
See Treatment and Medication for more detail.
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. [4] } More than 400 disease-causing mutations have been reported to date. [5]
Pathophysiology
The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated by protein and amino acid metabolism. [6] 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. [7] 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 results in an excess of both substrates for the reaction (see the image below).
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.
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.
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.
The long-term outlook for individuals with all forms of OTC deficiency is guarded, particularly with reference to cerebral function. [13]
Patient Education
Family pedigree studies in this disease are essential for the following 2 reasons:
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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.
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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.
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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.
