Congenital Urea Cycle Disorders

Written by Mary Ellen Ellis | Published on August 20, 2012
Medically Reviewed by George Krucik, MD

What Are Congenital Urea Cycle Disorders?

Congenital urea cycle disorders are genetic disorders that disrupt the body’s normal process of removing waste through urine. When waste is not removed properly, it builds up in the body and can cause serious illness.

There is no cure for this condition. Most urea cycle disorders are diagnosed in infancy and can be managed with treatment and a low-protein diet. However, certain factors such as stress and illness can aggravate the condition and cause complications. People with urea cycle disorders will need to carefully monitor and manage their condition throughout their lives.

What Is the Urea Cycle

The urea cycle is the process by which your body removes waste products, specifically excess nitrogen. When you eat proteins, they are broken down into smaller compounds called amino acids. When these proteins are not broken down properly they accumulate as ammonia.

Certain enzymes (molecules that catalyze chemical reactions) in your liver convert the waste ammonia into a molecule called urea. Urea can then be integrated into urine and excreted from your body. There are six enzymes that aid in this process; people with congenital urea cycle disorders are deficient in one of these enzymes. This deficiency disrupts the cycle and causes hyperammonemia (excessive buildup of ammonia in the bloodstream). High levels of ammonia in the body can lead to serious complications, including brain damage, coma, or even death.

Types of Congenital Urea Cycle Disorders

There are six types of enzyme disorders of the urea cycle that are usually recognized in infancy. These disorders are referred to by the names of the missing enzyme. These are:

  • argininosuccinate aciduria (ASL)
  • arginase deficiency (AG)
  • carbamoyl phosphate synthetase deficiency (CPS1)
  • citrullinemia (ASS1)
  • N-acetyl glutamate synthetase deficiency (NAGS)
  • ornithine transcarbamylase deficiency (OTC)

These disorders are autosomal recessive, meaning that both parents pass along a defective gene to a child. The only exception is ornithine transcarbamylase deficiency (OTC), which is inherited from the X chromosome of one parent. In rare cases OTC disorders occur as a result of spontaneous mutation in a developing fetus (NUCDF).

Symptoms of Congenital Urea Cycle Disorders

Congenital urea cycle disorders are present at birth. Children with severe deficiencies show symptoms within the first 24 hours of life, including:

  • irritability
  • sleepiness or trouble waking up
  • decreased desire to eat
  • vomiting

In severe cases, seizures, breathing difficulty, and coma may occur. The infant can die if the disorder is left untreated. Severe disorders in newborns are often associated with deficiencies in OTC, CPS1, or ASA enzymes.

People born with mild deficiencies may not show symptoms until early childhood. Late-onset symptoms often include:

  • refusal to eat high-protein foods
  • vomiting or nausea after meals high in protein
  • lethargy
  • agitation or hyperactive behavior

Diagnosis of Congenital Urea Cycle Disorders

Observation of symptoms is the first indicator that a baby may have a congenital urea cycle disorder. The presence of a disorder can be confirmed by taking samples of the infant’s blood and urine.

A blood test may show high levels of ammonia, amino acids, and other compounds indicative of a specific disorder. For example, high levels of orotic acid typically indicate deficiency of the OTC enzyme. High levels of amino acids in the urine also indicate a urea cycle disorder.

Infants may also receive a genetic test, which can pinpoint the enzyme affected and the specific disorder. A doctor may also take a biopsy of the liver. This involves removing a small piece of the liver to detect the absence of certain enzymes.

Treatment for Congenital Urea Cycle Disorders

Because congenital urea cycle disorders are genetic, there is no cure. Treatment involves a low-protein diet combined with other medications or supplements designed to help the body remove excess ammonia. Treatment must be monitored closely by a doctor or other health care provider to ensure that protein and other nutrient levels are appropriate for infants. The baby needs to get enough protein to grow; however, too much protein causes excessive ammonia production. A low-protein diet must be continued throughout life to control ammonia production. People with urea cycle disorders should not fast under any circumstances.

Medications such as sodium phenylbutyrate (Buphenyl) and sodium benzoate are often prescribed to help remove ammonia from the bloodstream. Other drugs, such as L-citrulline or L-arginine (naturally occurring amino acids), are prescribed to help catalyze the deficient enzymes. Supplement powders or pills may also be used to ensure that the body receives enough protein and amino acids.

Diet and drug treatment are not always enough to manage this condition. In very severe cases, liver transplant may be an option. While transplants are often successful in treating urea cycle disorders, this may create further medical problems, such as viral infections or delayed development (NUCDF).

Talk to your doctor about the benefits and risks associated with any form of treatment to decide which method is best for you and your family.

Outlook and Complications for Congenital Urea Cycle Disorders

The outlook for having a congenital urea cycle disorder depends on several factors:

  • the type of disorder
  • severity of the disorder
  • how early the disorder is diagnosed
  • how well a low-protein diet is followed

With early diagnosis and treatment the outlook is good. However, diet and treatment must be managed throughout a person’s life. Ammonia accumulation can also be triggered by illness (such as fever or injury) or stress. People living with urea cycle disorders have to take special care to manage stress and avoid illness as much as possible. Poor treatment or management of urea cycle disorders can lead to more serious medical conditions or death.

  • swelling in the brain
  • brain damage
  • coma
  • developmental disability
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