Hereditary urea cycle abnormality

The urea cycle is a process in which waste (ammonia) is removed from the body. When you eat proteins, the body breaks them down into amino acids. Ammonia is produced from leftover amino acids, and it must be removed from the body.

The liver produces several chemicals (enzymes) that change ammonia into a form called urea, which the body can remove in the urine. If this process is disturbed, ammonia levels begin to rise.

Several inherited conditions can cause problems with this waste-removal process. People with a urea cycle abnormality have an altered gene that makes the enzymes needed to break down ammonia in the body and so the enzyme doesn't function properly.

These conditions include:

• Argininosuccinic aciduria
• Arginase deficiency
• Carbamyl phosphate synthetase (CPS) deficiency
• Citrullinemia
• N-acetylglutamate synthetase (NAGS) deficiency
• Ornithine transcarbamylase (OTC) deficiency

As a group, these conditions occur in 1 in 30,000 newborns. OTC deficiency is the most common of these conditions.

Because OTC deficiency is an X-linked condition, boys are more often affected by it than girls. Girls are rarely affected with OTC. Those girls who are affected have milder symptoms and can develop symptoms of the condition later in life. Because they are autosomal recessive conditions, the other urea cycle abnormalities affect both girls and boys equally.

To get them, you need to receive a non-working copy of the gene from both parents. Sometimes parents don't know they carry a non-working copy of the gene until their child gets one of these conditions.

Typically, an affected baby begins nursing well and seems normal. However, over time the baby develops poor feeding, vomiting, and sleepiness, which may be so deep that the baby is difficult to awaken. This most often occurs within the first week after birth.

Symptoms include:

• Confusion
• Decreased food intake
• Deep and rapid breathing (hyperventilation)
• Increased sleepiness, difficulty waking up
• Nausea, vomiting
• Seizures

Symptoms of partial deficiencies of a urea cycle enzyme may present in later childhood or adulthood and may include:

• Anorexia
• Changes in mental status
• Irritability
• Hallucinations
• Headaches
• Irritability
• Uncoordinated movement (ataxia)
• Visual impairment

Your health care provider will often diagnose these conditions when the child is still an infant.

Signs may include:

• Abnormal amino acids in blood and urine
• Abnormal level of orotic acid in blood or urine
• High blood ammonia level
• Normal level of acid in blood

Tests may include:

• Arterial blood gas
• Blood ammonia
• Blood glucose
• Plasma amino acids
• Urine organic acids
• Genetic tests
• Liver biopsy
• MRI or CT scan

Limiting protein in the diet can help treat these conditions by reducing the amount of nitrogen waste the body produces. (The waste is in the form of ammonia.) Special low-protein infant and toddler formulas are available.

It is important that a provider guides the baby's protein intake. The provider can balance the amount of protein the baby gets so that it is enough for growth, but not enough to cause symptoms.

It is very important for people with these conditions to avoid fasting.

People with a urea cycle abnormality must also be very careful under times of physical stress, such as when they have infections. Stress, such as a fever, can cause the body to break down its own proteins. These extra proteins can make it hard for the abnormal urea cycle to remove the byproducts.

Develop a plan with your provider for when you are sick to avoid all protein, drink high carbohydrate drinks, and get enough fluids.

Most people with a urea cycle abnormality will need to stay in the hospital at some point. During such times, they may be treated with medicines that help the body remove nitrogen-containing wastes. Dialysis may help rid the body of excess ammonia during extreme illness. Some people may need a liver transplant.

• UCD in Common -- www.ucdincommon.com/keep-conitynected
• National Urea Cycle Disorders Foundation -- nucdf.org/
• Urea Cycle Disorders Consortium -- ucdc.rarediseasesnetwork.org/
• Connecting Families UCD Foundation -- www.ucdfamily.org/

How well people do depends on:

• Which urea cycle abnormality they have
• How severe it is
• How early it is discovered
• How closely they follow a protein-restricted diet

Babies diagnosed in the first week of life and put on a protein-restricted diet right away may do well.

Sticking to the diet can lead to normal adult intelligence. Repeatedly not following the diet or having stress-induced symptoms can lead to brain swelling and brain damage.

Major stresses, such as surgery or accidents, can be complicated for people with this condition. Extreme care is needed to avoid problems during such periods.

Complications can include:

• Coma
• Confusion and eventually disorientation
• Death
• Increase in blood ammonia level
• Swelling of the brain

Prenatal testing is available. Genetic testing before an embryo is implanted may be available for those using in vitro if the specific genetic cause is known.

A dietician is important to help plan and update a protein-restricted diet as the child grows.

As with most inherited conditions, there is no way to prevent them from developing after birth. If one or both parents are known to have one of these conditions, prenatal genetic testing to identify affected babies before they are born should be considered.

Teamwork between parents, the medical team, and the affected child to follow the prescribed diet can help prevent severe illness.

Abnormality of the urea cycle - hereditary; Urea cycle - hereditary abnormality

Kliegman RM, St Geme JW, Blum NJ, et al. Defects in metabolism of amino acids. In: Kliegman RM, St Geme JW, Blum NJ, et al, eds. Nelson Textbook of Pediatrics. 22nd ed. Philadelphia, PA: Elsevier; 2025:chap 105.

Konczal LL. Inborn errors of metabolism. In: Martin RJ, Fanaroff AA, eds. Fanaroff and Martin's Neonatal-Perinatal Medicine. 12th ed. Philadelphia, PA: Elsevier; 2025:chap 94.

Sen K, Nagamani SCS, Lichter-Konecki U. Urea cycle disorders. In: Ashwal S, Pearl PL, et al, eds. Swaiman's Pediatric Neurology: Principles and Practice. 7th ed. Philadelphia, PA: Elsevier; 2026:chap 60.

Updated by: Anna C. Edens Hurst, MD, MS, Associate Professor in Medical Genetics, The University of Alabama at Birmingham, Birmingham, AL. Review provided by VeriMed Healthcare Network. Also reviewed by David C. Dugdale, MD, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.