The urea cycle is a metabolic cycle involving incorporation of waste nitrogen from the breakdown of dietary proteins into a form (urea) that can be removed from the body.

The liver makes urea from nitrogen waste, which is then excreted in the urine. Several hereditary conditions can cause this problem. These are genetic diseases caused by a the lack of a gene to make critical enzymes needed for the urea cycle. They include:

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

As a group, these disorders occur in 1 in 30,000 newborns. Ornithine transcarbamylase deficiency is the most common. All are genetic diseases associated with lack of a protein/enzyme activity in the urea cycle.

Ornithine transcarbamylase deficiency is an X-linked recessive disorder (which will occur in all males who inherit the gene because they lack another X which could make up for it). Females are rarely affected -- those who are have milder symptoms and later onset.

The other types are inherited in an autosomal recessive manner, meaning that you need to get bad copies of the gene from both parents to develop the condition. Thus, they can appear in families which had no prior knowledge that parents were carriers.

As a result of these disorders, ammonia levels rise as proteins aren't broken down into urea and removed. If ammonia rises too high in the body it can cause symptoms, such as confusion. Untreated, this can progress to swelling of the brain, coma, and death.

The disorder is frequently diagnosed in infancy. Typically, the baby begins nursing well and seems normal. However, with time there is progressively poorer feeding, vomitting, and sleepiness which may be so deep that the baby is difficult to arouse.

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

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

The mainstay of treatment of 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-wastes.

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.

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 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.

NATIONAL UREA CYCLE DISORDERS FOUNDATION
4841 Hill Street; La Canada, CA 91011
Phone: 818-790-2460
Toll-Free: 1-800-38-NUCDF
http://www.nucdf.org/www.nucdf.org

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 well.

Continued adherence to the diet can lead to normal adult intelligence. 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

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.