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Phenylketonuria (PKU)


Glutaric Acidemia - Type 1


Glutaric Acidemia - Type 2




Isovaleric Acidemia


Maple Syrup Urine Disease (MSUD)


Propionic Acidemia


Methylmalonic Acidemia




Urea Cycle Disorders


Long Chain Fatty Acid Oxidation Disorders


Definitions of terms


Metabolic Conditions

Urea Cycle Disorders

The urea cycle is a metabolic cycle that converts waste nitrogen generated from the breakdown of dietary proteins into a form (urea) that can be removed from the body.
Waste nitrogen is carried in the blood as ammonia. This conversion of ammonia to urea occurs in the liver. Several genetic diseases or special groups of “birth defects” can cause this problem. These genetic diseases are caused by mistakes in the genes that make the critical enzymes of the urea cycle.
The urea cycle disorders include:

  • ornithine transcarbamylase deficiency (OTC)
  • citrullinemia
  • arginase deficiency
  • argininosuccinic aciduria
  • carbamyl phosphate synthetase (CPS) deficiency
  • N-acetyl glutamate synthetase deficiency (NAGS)

Alternative Names:
Abnormality of the urea cycle - hereditary; Urea cycle - hereditary abnormality; inborn error of metabolism

Causes, incidence, and risk factors:
As a group, these disorders occur in 1 in 30,000 newborns. Ornithine transcarbamylase deficiency is the most common. Arginase deficiency is the rarest.

Ornithine transcarbamylase deficiency is an X-linked disorder. This means the changed gene is on the X chromosome (women have two X chromosomes and men have one X chromosome). Because of this, males with this condition are more severely affected than females. Females with OTC deficiency can have no symptoms or can be as severe as males.

The other types are inherited in an autosomal recessive manner. This means that to have the disease, the patient has to inherit a changed copy of the gene from both the mother and father. The parents, however, are called carriers and do not have symptoms of the disease. Thus, the first diagnosis of one of the autosomal recessive types may occur without prior knowledge that parents were carriers or that the disease runs in the family.

As a result of these disorders, ammonia levels can rise especially with the first or subsequent feeding of protein. If ammonia rises too high in the body it can cause symptoms, such as confusion and lethargy. Untreated, this can progress to swelling of the brain, coma, and death.

The disorder is frequently diagnosed in infancy especially in the more severe cases. Typically, the newborn baby begins nursing well and seems normal. However, within as little as 24-72 hours after the first feeds, there is progressively poorer feeding, vomiting, and sleepiness which may be so deep that the baby is difficult to arouse. However, milder cases may present differently and at a later time.


  • disliking protein-containing foods
  • decreased food intake
  • nausea, vomiting
  • change in clarity of mind, confusion
  • increased sleepiness, difficulty arousing person
  • coma
  • agitation

Signs and tests:

  • elevated blood ammonia level
  • abnormal pattern of blood and urine amino acids
  • abnormal level of orotic acid in urine
  • normal level of organic acid in urine
  • low level of enzyme activity in liver biopsy
  • abnormal genetic test result, DNA mutation(s) present in one of genes for the proteins of the urea cycle
  • MRI or CT scan may show swelling of brain

The mainstay of treatment for these disorders is PROTEIN RESTRICTION. As protein is the source of nitrogen-containing chemicals in the diet, limiting protein will limit the amount of nitrogen-waste. This reduces the stress on the hampered urea cycle. It is imperative that protein restriction be done with guidance from a health care professional who can make certain to balance the amount of protein needed for growth with that which will cause symptoms.

It is extremely important for people with these disorders to AVOID FASTING.

Two other important ways to treat these conditions are to use medications that dispose of waste nitrogen by different routes and to supplement with special amino acids which may be deficient in the body.

Patients with urea cycle abnormalities must also be very careful under times of stress, such as infections. Stress, such as fever, can cause the body to break down its own proteins and exceed the capacity of the abnormal urea cycle to dispose of the by-products.

A sick-day plan should be formulated with your doctor to avoid all protein, consume high carbohydrate drinks, and stay hydrated.

Most patients with urea cycle disorders require hospitalization at some point in their illness. During such times, they may be treated with stronger medicines that help the body dispose of nitrogen-containing wastes. Dialysis may be required to help rid the body of excess ammonia during extreme illness.

Support Groups:
4841 Hill Street; La Canada, CA 91011
Phone: 818-790-2460
Toll-Free: 1-800-38-NUCDF

Expectations (prognosis):
The outcome depends on which of the urea cycle abnormalities a person has, how severe it is, how early it is discovered, and how closely the protein-restricted diet is followed. Babies diagnosed in the first week of life and are immediately placed on a diet do better. Elevated ammonia level is an emergency since we know the longer a patient has elevated ammonias, the more brain damage can occur.

Continued adherence to the diet after rapid diagnosis can lead to normal adult intelligence in some cases. Repeated episodes of not following the diet or stress-induced symptoms can lead to repeated brain swelling and irreversible brain damage.

It should be expected that major stresses, such as surgery or accidents, can be complicated for these patients. Extreme care is required to avoid problems during such periods.


  • confusion progressing to disorientation
  • coma
  • death
  • repeated increases in blood ammonia level

Calling your health care provider:
If your child has a test which shows increased ammonia in the blood, request an evaluation by a biochemical geneticist or metabolic specialist. If there is a family history of urea cycle disorder, seek genetic counseling during family planning. A dietician is instrumental in planning and updating a protein-restricted diet as a child grows.

As with most inherited diseases, there is no way to absolutely prevent these disorders. Prenatal testing is available. Preimplantation genetic testing may be available for those using in vitro fertilization.
Preventing the episodes of severe illness, for example -- requiring hospitalization at times of stress, can often be managed by teamwork between parents, the affected child, and doctors.

Update Date: 6/4/2004
Updated by: Brendan Lee, M.D., Baylor College of Medicine, Houston, TX. Update provided by National Urea Cycle Disorder Foundation.

Review Date: 2/9/2002
Reviewed By: David G. Brooks, M.D., Ph.D., Division of Medical Genetics, University of Pennsylvania Medical Center, Philadelphia, PA. Review provided by VeriMed Healthcare Network.


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