Carbamoyl phosphate synthetase I deficiency is an inherited disorder that causes ammonia to accumulate in the blood (hyperammonemia). Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The brain is especially sensitive to the effects of excess ammonia.

In the first few days of life, infants with carbamoyl phosphate synthetase I deficiency typically exhibit the effects of hyperammonemia, which may include unusual sleepiness, poorly regulated breathing rate or body temperature, unwillingness to feed, vomiting after feeding, unusual body movements, seizures, or coma. Affected individuals who survive the newborn period may experience recurrence of these symptoms if diet is not carefully managed or if they experience infections or other stressors. They may also have delayed development and intellectual disability.

In some people with carbamoyl phosphate synthetase I deficiency, signs and symptoms may be less severe and appear later in life.

Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. The CPS1 gene provides instructions for making the enzyme carbamoyl phosphate synthetase I. This enzyme participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle processes excess nitrogen, generated when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys. The specific role of the carbamoyl phosphate synthetase I enzyme is to control the first step of the urea cycle, a reaction in which excess nitrogen compounds are incorporated into the cycle to be processed.

Carbamoyl phosphate synthetase I deficiency belongs to a class of genetic diseases called urea cycle disorders. In this condition, the carbamoyl phosphate synthetase I enzyme is at low levels (deficient) or absent, and the urea cycle cannot proceed normally. As a result, nitrogen accumulates in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of carbamoyl phosphate synthetase I deficiency.

Normal Function

The CPS1 gene provides instructions for making the enzyme carbamoyl phosphate synthetase I. This enzyme participates in the urea cycle, a series of reactions that occurs in liver cells. The urea cycle processes excess nitrogen, generated when protein is used by the body, into a compound called urea that is excreted by the kidneys. Excreting the excess nitrogen prevents it from accumulating in the form of ammonia, which is toxic.

The specific role of carbamoyl phosphate synthetase I is to control the first step of the urea cycle, a reaction in which excess nitrogen compounds are incorporated into the cycle to be processed.

Health Conditions Related to Genetic Changes

Carbamoyl phosphate synthetase I deficiency

Approximately 10 mutations that cause carbamoyl phosphate synthetase I deficiency have been identified in the CPS1 gene. A mutated CPS1 gene may result in a carbamoyl phosphate synthetase I enzyme that is shorter than normal or the wrong shape, or may prevent the enzyme from being produced at all.

The shape of an enzyme affects its ability to control a chemical reaction. If the carbamoyl phosphate synthetase enzyme is misshapen or missing, it cannot fulfill its role in the urea cycle. Excess nitrogen is not converted to urea for excretion, and ammonia accumulates in the body. Ammonia is toxic, especially to the nervous system, so this accumulation causes neurological problems and other signs and symptoms of carbamoyl phosphate synthetase I deficiency.

Other disorders

One common alteration (polymorphism) in the CPS1 gene has been associated with increased risk of circulatory problems in newborns and in individuals who have received bone marrow transplants. This genetic change results in the amino acid (protein building block) asparagine being substituted for the amino acid threonine at position 1405 in the protein sequence (written as Thr1405Asn or T1405N).

Researchers believe that this polymorphism in the CPS1 gene may reduce the production of a compound called nitric oxide (NO). Normally, nitric oxide causes blood vessels to expand (dilate), which reduces blood pressure. A reduced amount of nitric oxide could lead to circulatory problems.

Other Names for This Gene

• carbamoyl phosphate synthase I
• carbamoyl-phosphate synthase 1, mitochondrial
• carbamoyl-phosphate synthase, mitochondrial precursor
• carbamoylphosphate synthetase I
• CPSase I
• CPSM_HUMAN

Genomic Location

CPS I deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• CPS I deficiency is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking CPS1 gene to their baby. Only babies with two nonworking CPS1 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the CPS1 gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the CPS1 gene, they have a 1 in 4 chance of having a child with CPS I deficiency.
  • Carriers for CPS I deficiency often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with CPS I deficiency.
  • Parents who already have a child with CPS I deficiency still have a 1 in 4 chance of having another child with CPS I deficiency. This 1 in 4 chance stays the same for future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of CPS I deficiency can usually be seen within the first few days of life.

Signs of the condition may include the following:

• Weak muscle tone (hypotonia)
• High levels of ammonia (hyperammonemia)
• Poor feeding
• Sleepiness or lack of energy (lethargy)
• Vomiting, especially after eating
• Breathing trouble
• Seizures

Newborn screening for CPS I deficiency requires collecting a small amount of blood from your baby’s heel. Screening measures how much citrulline is in your baby’s blood. Citrulline is one of the products of the urea cycle and does not get formed when the CPS I enzyme is not working. Babies with very low levels of citrulline might have CPS I deficiency.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for CPS I deficiency is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Screening samples collected too early (before the baby is 24 hours of age) may cause false positive results. Babies with other conditions that have low citrulline levels may also be detected through this screening. An example of another condition that may be detected is ornithine translocase (OTC) deficiency.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Diet low in protein
• Special foods or formulas
• Arginine and citrulline supplements
• Medications
• Dialysis
• Liver transplant

Early and ongoing treatment can be lifesaving and can lead to better growth and development.

Carbamoyl phosphate synthetase I deficiency is a rare disorder; its overall incidence is unknown. Researchers in Japan have estimated that it occurs in 1 in 800,000 newborns in that country.