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Urea Cycle Disorders

Urea cycle disorders

Definition

Urea cycle disorders are inborn errors in metabolism that can lead to brain damage and death. They involve a deficiency in one of the enzymes required by the urea cycle that removes ammonia from the blood.

Description

Ammonia accumulates in toxic levels if the urea cycle does not convert nitrogen from protein metabolism into urea for excretion into the urine. A series of biochemical reactions are necessary to complete the urea cycle. When an enzyme is missing or deficient, the cycle is interrupted and nitrogen accumulates in the form of ammonia. It cannot be excreted from the body and enters the bloodstream, damaging nervous tissues, including the brain.

Seizures, poor muscle tone, respiratory distress, and coma follow if an affected infant is not treated. Acute neonatal symptoms are most frequently seen in boys with ornithine transcarbamylase, or OTC, deficiency. Mental retardation and even death may follow. People with partial deficiencies may not discover the problem until childhood or adulthood. Children may avoid meat or other protein foods. As ammonia levels rise in the body, individuals begin to show lethargy and delirium. Left untreated they may suffer a coma or death.

Sometimes young people with urea cycle disorders who go undiagnosed begin to show behavioral and eating problems. Those with partial enzyme deficiencies may experience episodes of high ammonia levels in the blood. This can occur after suffering from viral illnesses including chicken pox, or after eating high-protein meals, or even after significant physical exertion.

The incidence of adults with urea cycle disorders is increasing. Recent evidence has indicated that some people have survived undiagnosed into adulthood. They can suffer stroke-like symptoms, lethargy, and delirium. Without proper diagnosis and treatment, adults are at risk for permanent brain damage, coma, and death. Symptoms can appear after giving birth or after contracting a virus, and some adults have shown deficiencies after using the medication valproic acid (an anti-epileptic drug). Adult onset is more common in women with OTC deficiency.

Different enzymes may be lacking in the various forms of urea cycle disorders. The six major disorders of the urea cycle include:

  • CPS–Carbamyl Phosphate Synthetase
  • NAGS–N-Acetylglutamate Synthetase
  • OTC–Ornithine Transcarbamylase
  • ASD–Argininosuccinic Acid Synthetase (Citrullinemia)
  • ALD–Argininosuccinase Acid Lyase (Argininosuccinic Aciduria)
  • AG–Arginase

Genetic profile

All of these disorders are inherited as autosomal recessive traits except for ornithine transcarbamylase (OTC) deficiency. It is inherited as an X-linked trait, from the mother.

Demographics

It is estimated the incidence of urea cycle disorders is about one in 30,000 births. Males and females are affected equally, except for the OTC deficiency which is more prevalent in males due to the fact that it is an X-linked disorder.

Signs and symptoms

In severe urea cycle disorders, rising ammonia levels cause irritability, vomiting and lethargy within the first 24–72 hours of life. Seizures, poor muscle tone, respiratory distress, and coma follow if the infant is not treated. Acute neonatal symptoms are most frequently seen in boys with ornithine transcarbamylase or OTC deficiency. However, patients with mild or moderate urea cycle enzyme deficiencies may not show symptoms until early childhood.

Diagnosis

Early detection through blood testing is essential to prevent irreversible brain damage in severe cases of urea cycle disorders.

Treatment and management

Therapy consists of eating a diet that provides enough protein so the body gets the essential amino acids needed for growth, but not so much that toxic levels of ammonia are formed. Treatment may entail a protein restricted diet together with medications that provide alternative pathways for the removal of ammonia from the blood. These medications tend to be unpalatable and may be given by way of tube feedings. Blood tests are needed to monitor levels of ammonia, and hospitalizations may become necessary if levels rise to high.

Prognosis

With early detection and proper diet restrictions, individuals can lead relatively normal lives. However, irreversible brain damage can develop quickly in severe cases that go undetected.

Resources

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

National Urea Cycle Disorders Foundation. 4841 Hill St., La Canada, CA 91001. (800) 38-NUCDF.

Julianne Remington

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