Overview of Urea Cycle Disorders

Our diet supplies the amino acids and proteins that are very essential for normal growth and functions of our body. These amino acids and proteins contain nitrogen and when they are broken down, the nitrogen has to be disposed. The urea cycle is a pathway that is essential to get rid of excess waste nitrogen from the body. The enzymes (proteins that speed up the making or breaking of compounds) and the transporters (channels that allow proteins to move within the cells of the body) of the urea cycle help convert this waste nitrogen from ammonia (a toxic product produced by the body) into urea. In urea cycle disorders, there is a deficiency of one of the six enzymes (NAGS, CPS1, OTC, ASS1, ASL, and ARG1) or two transporters (ORNT1 and Citrin) required to make urea, and the inability to dispose of nitrogen leads to a toxic build up of ammonia. Children with severe forms of urea cycle disorders can present within the first few days of life whereas those with milder forms may present later in childhood, and some even in adulthood.

Symptoms

Newborn babies

Newborn babies can present with symptoms due to increased blood levels of ammonia (hyperammonemia). The initial symptoms of hyperammonemia in the newborn period are often non-specific and include:

  • failure to feed
  • vomiting
  • inability to maintain normal body temperature
  • drowsiness
  • symptoms may progress from drowsiness to lethargy and if untreated can lead to coma

Any Age

Milder (or partial) urea cycle enzyme deficiencies typically present after the newborn period and symptoms can occur almost anytime of life. The recognition of these forms might be delayed for months or even years. Episodes of hyperammonemia may be triggered by illness or stress. The hyperammonemic episodes are frequently 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,
  • (hallucinations) perception of something (as a visual image or a sound) with no external cause,
  • (psychosis) loss of touch with reality
  • Changes may be seen on an electroencephalogram (a test to record brain electrical activity) or brain imaging like magnetic resonance imaging (MRI).
 

Diagnosis/Testing

Elevated blood ammonia is a strong indicator for the presence of a urea cycle disorders. Analysis of the blood levels of acids can be used to diagnose a specific urea cycle disorder. Many urea cycle disorders can be definitively diagnosed based on measuring amino acids alone (for example argininosuccinic aciduria due to deficiency of the enzyme ASL), whereas this may not be the case for other urea cycle disorders (e.g., CPS1 deficiency). A definitive diagnosis of urea cycle disorder is made using a combination of the following:

  • family history
  • clinical presentation
  • analysis of amino acid in the blood
  • levels of orotic acid in the blood
  • genetic testing
  • enzyme activity from a liver biopsy, skin biopsy or red blood cells
 

Treatment

The primary goals of the treatment are to prevent the build up of ammonia and if this were ever to happen, initiate treatment in the hospital to rapidly decrease the levels of ammonia. These are typically accomplished by:

  • Dietary therapy that consists of reducing the amount of protein in the diet
  • Providing supplements that contain essential amino acids and other nutrients
  • Supplement with nutrients like arginine or citrulline that help decrease ammonia
  • Treatment with medications that help in the excretion of ammonia

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