Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with argininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have a poorly controlled breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and intellectual disability. Progressive liver damage, high blood pressure (hypertension), skin lesions, and brittle hair may also be seen.

Occasionally, individuals may inherit a mild form of the disorder. These individuals can have an accumulation of ammonia in the bloodstream only during periods of illness or other stress, or mild intellectual disability or learning disabilities with no evidence of elevated ammonia levels.

Mutations in the ASL gene cause argininosuccinic aciduria. This condition belongs to a class of genetic diseases called urea cycle disorders because they are caused by problems with a process in the body called the urea cycle. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle breaks down excess nitrogen, which is made when protein is used by the body, to make a compound called urea. Urea is removed from the body in urine. Breaking down excess nitrogen and excreting it as urea prevents it from accumulating in the body as ammonia.

The ASL gene provides instructions for making an enzyme called argininosuccinate lyase, which is needed for the fourth step of the urea cycle. The specific role of the argininosuccinate lyase enzyme is to start the reaction in which the amino acid arginine, a building block of proteins, is produced from argininosuccinate, the molecule that carries the waste nitrogen collected earlier in the urea cycle. The arginine is later broken down into urea, which is excreted, and ornithine, which restarts the urea cycle.

In people with argininosuccinic aciduria, argininosuccinate lyase is dysfunctional or missing. As a result, the urea cycle cannot proceed normally, arginine is not produced, and nitrogen is not broken down efficiently. The excess nitrogen accumulates in the blood in the form of ammonia. This buildup of ammonia damages the brain and other tissues and causes neurological problems and other signs and symptoms of argininosuccinic aciduria. It is unclear how a lack of arginine contributes to the features of this condition.

Normal Function

The ASL gene provides instructions for making the enzyme argininosuccinate lyase. This enzyme primarily participates in the urea cycle, a series of reactions that occur in liver cells. The urea cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. Excreting the excess nitrogen prevents it from accumulating in the form of ammonia.

The specific role of the argininosuccinate lyase enzyme is to start the reaction in which the amino acid arginine, a building block of proteins, is produced from argininosuccinate, the molecule that carries the waste nitrogen collected earlier in the urea cycle. The arginine is later broken down into urea, which is excreted, and ornithine, which restarts the urea cycle.

In cells throughout the body, the argininosuccinate lyase enzyme is also involved in moving (transporting) arginine into cells to make a compound called nitric oxide. Nitric oxide is important for regulating blood flow and blood pressure.

Health Conditions Related to Genetic Changes

Argininosuccinic aciduria

More than 130 mutations in the ASL gene have been found to cause argininosuccinic aciduria. In some cases, a short sequence of DNA is deleted from the gene. Other mutations replace one protein building block (amino acid) with another amino acid in the argininosuccinate lyase enzyme. In people of Arab ancestry, two common mutations replace the amino acid glutamine with a premature stop signal at position 116 (written as Gln116Ter or Q116*) or position 354 (written as Gln354Ter or Q354*) in the argininosuccinate lyase enzyme. Mutations in the ASL gene may result in an argininosuccinate lyase enzyme that is unstable, misshapen, or quickly broken down.

If the argininosuccinate lyase enzyme is misshapen or missing, it cannot fulfill its role in the urea cycle. Arginine is not produced, excess nitrogen is not converted to urea for excretion, and ammonia accumulates in the body. This buildup of ammonia damages the brain and other tissues and causes neurological problems and other signs and symptoms of argininosuccinic aciduria. It is unclear how a lack of arginine contributes to the features of this condition.

Other Names for This Gene

• Argininosuccinase
• Arginosuccinase
• arginosuccinate lyase
• ARLY_HUMAN

Genomic Location

Argininosuccinic aciduria is a genetic condition. Babies inherit it from their biological (birth) parents.

• Argininosuccinic aciduria is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking ASL gene to their baby. Only babies with two nonworking ASL genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ASL 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 ASL gene, they have a 1 in 4 chance of having a child with argininosuccinic aciduria.
  • Carriers for argininosuccinic aciduria 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 argininosuccinic aciduria.
  • Parents who already have a child with argininosuccinic aciduria still have a 1 in 4 chance of having another child with argininosuccinic aciduria. 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.

Signs of argininosuccinic aciduria most often appear shortly after birth (within a few days of birth). Rarely, some babies have a mild type of argininosuccinic aciduria where signs do not start until childhood. These signs may be triggered by eating foods high in protein, going a long time without eating (prolonged fasting), illnesses, and infections.

Signs of the condition may include the following:

• High levels of ammonia (hyperammonemia)
• Poor feeding
• Sleepiness or lack of energy (lethargy)
• Vomiting
• Tight, rigid muscles (spasticity)
• Breathing trouble
• Seizures
• Coma

Newborn screening for argininosuccinic aciduria is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called amino acids) are in your baby’s blood. Amino acids are produced when your body breaks down proteins. Babies with argininosuccinic aciduria cannot break down two amino acids called citrulline and argininosuccinic acid. Babies with high levels of these substances might have argininosuccinic aciduria.

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

If your baby’s blood spot screening result for argininosuccinic aciduria 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 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

Children who receive early and ongoing treatment for argininosuccinic aciduria can have healthy growth and development.

Argininosuccinic aciduria occurs in approximately 1 in 70,000 to 218,000 newborns. Most cases of this condition are detected shortly after birth by newborn screening.