eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Ornithine Transcarbamylase Deficiency

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Contributor Information and Disclosures

Updated: Aug 23, 2007

Introduction

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

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.

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