The Urea Cycle Disorders Consortium
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Urea Cycle Disease Overview:

In urea cycle disorders (UCD), the patient has a severe deficiency or is missing any of the first four enzymes (CPSI, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) [Batshaw 1984, Summar 2001, Summar & Tuchman 2001]. Enzymes are proteins that are produced by living cells and regulate the body’s process to breakdown products, such as ammonia. Ammonia is a product of protein digestion and the urea cycle is required for the body to excrete ammonia. In patients with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years. Early in life, infants with urea cycle disorders develop toxic levels of ammonia build-up in the blood.

Symptoms

Newborn Children

Initial symptoms of hyperammonemia (too much ammonia in the blood) in the newborn are non-specific:

  • failure to feed,
  • inability to maintain normal body temperature with a low core body temperature,
  • drowsiness
  • symptoms progress from sleepiness to abnormal drowsiness and coma [Brusilow 1985, Batshaw & Berry 1991, Summar 2001].

Symptoms may progress in the newborn that appears normal but rapidly develops cerebral edema (swelling of the brain). Symptoms of cerebral edema include the following:

  • (lethargy) abnormal drowsiness
  • (anorexia) loss of appetite
  • breathing too fast or too slow
  • (hypothermia) low body temperature
  • seizures
  • neurologic posturing (abnormal body position due to brain toxicity)

Any Age

Milder (or partial) urea cycle enzyme deficiencies can be triggered by illness or stress at almost any time of life resulting in multiple mild elevations ammonia in the blood. The first recognized clinical episode may be delayed for months or years. [Bourrier et al 1988] Hyperammonemic episode (too much ammonia in the blood) is marked by the following:

  • loss of appetite,
  • repeated vomiting,
  • (lethargy) abnormal drowsiness,
  • abnormal behavior,
  • (sleep disorders) difficulty falling or staying asleep, falling asleep at inappropriate times, excessive total sleep time, or abnormal behaviors associated with sleep ,
  • (delusions) a false belief in things that are not true despite the facts,
  • (hallucinations) perception of something (as a visual image or a sound) with no known external cause,
  • (psychosis) loses touch with reality

Diagnosis/Testing

An elevated blood ammonia is a strong indication for the presence of a UCD. Amino acid analysis can be used to diagnose a specific urea cycle disorder. The amino acid arginine may be reduced in all urea cycle disorders, except arginase deficiency, in which it is elevated. A definitive diagnosis of CPSI deficiency, OTC deficiency, or NAGS deficiency is determined using the following:

  • family history,
  • clinical presentation,
  • amino acid and orotic acid testing (lab tests),
  • molecular genetic testing (lab tests),
  • enzyme activity from a liver biopsy specimen or red blood cells (arginase)

Treatment Schedule:

  • reducing the amount of ammonia in the blood
  • medication to assist excretion of the ammonia
  • reducing the amount of nitrogen in the diet
  • introduction of calories supplied by carbohydrates and fat
  • reducing the risk of brain damage