The condition is caused by a change in the ASS1 gene. This gene gives your body instructions for making the enzyme arginosuccinate synthase I. This enzyme helps the urea cycle remove the ammonia produced when your body breaks down proteins.

Without a working ASS1 gene, your baby cannot make enough working enzyme. As a result, their body has trouble getting rid of ammonia. High levels of ammonia are very dangerous.

Normal Function

The ASS1 gene provides instructions for making an enzyme called argininosuccinate synthase 1. This enzyme participates in the urea cycle, which is a sequence of chemical reactions that takes place in liver cells. The urea cycle processes excess nitrogen that is generated as the body breaks down proteins. The excess nitrogen is used to make a compound called urea, which is excreted from the body in urine.

Argininosuccinate synthase 1 is involved in the third step of the urea cycle. This step combines two protein building blocks (amino acids), citrulline and aspartate, to form a molecule called argininosuccinic acid. A series of additional chemical reactions uses argininosuccinic acid to form urea.

Health Conditions Related to Genetic Changes

Citrullinemia

At least 118 mutations that cause type I citrullinemia have been identified in the ASS1 gene. Type I citrullinemia is a serious condition that usually appears in the first few days of life. It causes life-threatening health problems, including poor feeding, vomiting, seizures, and loss of consciousness. Most of the mutations involved in type I citrullinemia change single amino acids in the argininosuccinate synthase 1 enzyme. These genetic changes likely alter the structure of the enzyme, impairing its ability to attach to molecules such as citrulline and aspartate. A few mutations lead to the production of an abnormally short version of the enzyme that cannot effectively play its role in the urea cycle.

Defects in argininosuccinate synthase 1 disrupt the third step of the urea cycle, preventing the liver from processing excess nitrogen into urea. As a result, nitrogen (in the form of ammonia) and other byproducts of the urea cycle (such as citrulline) build up in the bloodstream. Ammonia is toxic, particularly to the nervous system. An accumulation of ammonia during the first few days of life leads to poor feeding, vomiting, seizures, and the other signs and symptoms of type I citrullinemia.

Other Names for This Gene

• argininosuccinate synthetase 1
• ASS
• ASSY_HUMAN
• Citrulline-aspartate ligase
• CTLN1

Genomic Location

Citrullinemia, type I is a genetic condition. Babies inherit it from their biological (birth) parents.

• Citrullinemia, type I is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking ASS1 gene to their baby. Only babies with two nonworking ASS1 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ASS1 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 ASS1 gene, they have a 1 in 4 chance of having a child with citrullinemia, type I.
  • Carriers for citrullinemia, type I 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 citrullinemia, type I.
  • Parents who already have a child with citrullinemia, type I still have a 1 in 4 chance of having another child with citrullinemia, type I. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

• Headaches
• Vomiting
• Sleepiness
• Poor appetite
• Slurred speech
• Poor coordination

Newborn screening for citrullinemia, type I is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of a substance called citrulline is in your baby’s blood. When the urea cycle is not working well, citrulline builds up. Babies with high levels of citrulline might have citrullinemia, type I.

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

If your baby’s blood spot screening result for citrullinemia, type I 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 very soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. However, screening samples collected too early (before the baby is 24 hours old) may affect the results of screening.

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:

• Drugs that help remove ammonia from the body
• Diet low in protein
• Arginine supplements to help lower ammonia levels
• Liver transplant

Children who receive early and ongoing treatment for citrullinemia, type I can have healthy growth and development.

Type I citrullinemia is the most common form of the disorder, affecting about 1 in 57,000 people worldwide. Type II citrullinemia is found primarily in the Japanese population, where it occurs in an estimated 1 in 100,000 to 230,000 individuals. Type II also has been reported in other populations, including other people from East Asia, the Middle East, the United States, and the United Kingdom.