What are urea cycle disorders?

When our bodies break down proteins, ammonia is naturally produced. Usually, our bodies know to convert the ammonia to urea and then get rid of (excrete) it through peeing (urination). This is called the urea cycle.

But when a child has a urea cycle disorder, they don’t have one or more of the enzymes they need to tell their body to convert ammonia to urea. Ammonia then builds up to a toxic level. This can cause organ damage, particularly in the brain and the liver. 

Depending on how well your child’s enzymes are working, their symptoms could range from mild to severe.

Urea cycle disorders relate to deficiencies of one or more of these enzymes:

• N-acetylglutamate synthase (NAGS)
• Carbamoyl phosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinate synthetase (ASS) – this deficiency is called citrullinemia type I (CTLN 1)
• Argininosuccinate lyase (ASL) – this deficiency is called argininosuccinic aciduria 
• Arginase deficiency

Causes of urea cycle disorders

Urea cycle disorders are genetic conditions caused by changes in one of the many genes responsible for the urea cycle. These genes provide instructions to produce enzymes that convert ammonia into urea, which can be excreted in urine. If your child's body does not make enough of one or more of these enzymes, ammonia builds up in the body, which is toxic to the brain and the liver.

Most urea cycle disorders are inherited autosomal recessively. That means your child would have to inherit a defective gene from both parents to have this condition. 

 The specific genes responsible for these conditions are:

• N-acetylglutamate synthase (NAGS) deficiency – NAGS
• Carbamoyl phosphate synthetase I deficiency – CPS1
• Citrullinemia type I – ASS1
• Argininosuccinic aciduria (ASL deficiency) – ASL
• Arginase deficiency – ARG1

OTC deficiency is the most common urea cycle disorder. OTC deficiency is “X-linked” because the altered gene is only on the X chromosome.

Because boys typically only have one X chromosome, they will be affected if that gene is altered. 

Girls typically have two X chromosomes, so even if one copy of the gene is altered, they may experience a range of symptoms from unaffected to severe disease.

Signs and symptoms of urea cycle disorders

Symptoms of urea cycle disorders usually appear shortly after a child is born. Because both breastmilk and formula contain protein, ammonia can build up quickly in the first few days of life. 

High ammonia levels in newborns can be life-threatening. Symptoms can include:

• Failure to feed
• Seizures
• Lethargy
• Coma

For older children, high ammonia levels are often triggered by illness, fever, decreased food intake, strenuous exercise and/or psychological stress. These episodes may lead to:

• Behavioral abnormalities
• Sleep disorders
• Hallucinations and psychosis 
• Brain swelling 

Girls with OTC deficiency may range from having no symptoms to having severe episodes of high ammonia levels. Often, women who carry OTC deficiency will say they experience “brain fog” after consuming high-protein meals and tend to avoid eating meat.

Arginase deficiency causes less frequent high ammonia levels. Children with this disorder can have other neurological symptoms including:

• Tremors
• Difficulty with muscle coordination (ataxia)
• Smaller stature than their peers

Testing and diagnosis for urea cycle disorders

Some urea cycle disorders are discovered through newborn screening tests, which help to identify affected children shortly after birth. A simple heel prick is used to get a sample of your baby’s blood, which is then sent for testing.

Because these disorders are rare, newborn screening for them is not mandatory in many states. 

Currently, Pennsylvania screens newborns for argininosuccinic aciduria and citrullinemia. New Jersey and Delaware both screen for argininemia, argininosuccinic aciduria and citrullinemia type 1. 

In states that do not test newborns for urea cycle disorders, diagnosis typically comes after symptoms develop and your child is evaluated. This includes taking a patient history, a physical exam and blood or urine tests. 

Diagnosis of a urea cycle disorder is typically established in those who have:

• Elevated ammonia levels with a pattern of amino acids consistent with a specific disorder
• Pathogenic genetic variants identified through genetic sequencing

Treatment for urea cycle disorders

Urea cycle disorders have no cure, but they can be treated.  Symptoms will require lifelong management. The most important treatment is to restrict the amount of protein in your child’s diet, to help avoid the toxic buildup of ammonia. 

The main treatment for urea cycle disorders includes: 

• Eating a low-protein diet that focuses on fruits, vegetables and starches
• Supplementing with amino acids such as arginine and citrulline, which help the body break down ammonia
• Taking medications known as “nitrogen scavengers,” which decrease the amount of nitrogen in the body before it’s converted to ammonia 
• Regular blood testing to monitor ammonia levels in the blood

If your child has a sudden and significant increase in ammonia levels, dialysis is sometimes needed to reduce their ammonia levels quickly. 

In rare cases, a liver transplant may be recommended as a definitive treatment for urea cycle disorders. The transplanted liver would be able to produce the missing enzymes, making the transplant curative. However, liver transplantation carries its own risk and would not reverse damage that may have already occurred in the brain.

Follow-up care for urea cycle disorders

Patients treated for urea cycle disorders at Children’s Hospital of Philadelphia (CHOP) are monitored regularly at the Metabolic Disease Program, and followed by other subspecialists such as neuropsychology and gastroenterology. 

CHOP is currently conducting clinical trials and researching new therapies for urea cycle disorders. You can see our research studies here. An area that shows great promise is cell and gene therapy. 

Cell and gene therapy is an innovative and cutting-edge approach to treating certain genetic disorders like urea cycle disorders. Researchers at CHOP have pioneered some of the first FDA-approved cell and gene therapies for use in children. And we continue to investigate new ways of treating – and potentially curing – genetic disorders in children.

Learn how CHOP is making cell and gene therapy breakthroughs and which FDA-approved therapies are available at CHOP.