Ornithine Transcarbamylase (OTC) Deficiency Clinical Presentation

Updated: Jan 07, 2019
  • Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Clinical presentation of ornithine transcarbamylase (OTC) deficiency 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. [8, 9]  More often, heterozygous females are asymptomatic or may experience a severe migrainelike headache in association with excessive protein intake. [3]

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 [2]

  • 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.




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.


Tachypnea or hyperpnea may be present. Apnea and respiratory failure may occur in the latter stages of disease progression.


Hepatomegaly may be present and is usually mild.


Neurologic findings include the following:

  • Poor coordination

  • Dysdiadochokinesia

  • Hypotonia or hypertonia

  • Ataxia

  • Tremor

  • Seizures and hypothermia

  • Lethargy that progresses to combativeness, obtundation, and coma

  • Decorticate or decerebrate posturing



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 2015, more than 400 different gene alterations have been described; of those alterations, 149 are associated with neonatal-onset disease. [10, 5] 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.