Arginase deficiency is an inherited disorder that causes the amino acid arginine (a building block of proteins) and ammonia to accumulate gradually in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Arginase deficiency usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, intellectual disability, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.

In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life.

Mutations in the ARG1 gene cause arginase deficiency.

Arginase deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.

The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency.

Normal Function

The ARG1 gene provides instructions for producing the enzyme arginase. This enzyme participates in the urea cycle, a series of reactions that occurs in liver cells. The urea cycle processes excess nitrogen, which is generated when proteins and their building blocks (amino acids) are used by the body. Through the urea cycle, excess nitrogen is made 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.

Arginase controls the last step of the urea cycle, a reaction in which nitrogen is removed from the amino acid arginine and processed into urea for excretion from the body. A compound called ornithine is also produced in this reaction; it is needed for the urea cycle to repeat.

Health Conditions Related to Genetic Changes

Arginase deficiency

Approximately 12 mutations have been identified in the ARG1 gene. A mutated ARG1 gene may result in an arginase enzyme that is unstable, shorter than usual 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 arginase 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 and arginine accumulate in the body. Ammonia is toxic, especially to the nervous system, and the accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency.

Other Names for This Gene

• A-I
• ARGI1_HUMAN
• arginase, liver
• arginase, type I

Genomic Location

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

• Arginase deficiency is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking ARG1 gene to their baby. Only babies with two nonworking ARG1 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ARG1 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 ARG1 gene, they have a 1 in 4 chance of having a child with arginase deficiency.
  • Carriers for arginase 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 arginase deficiency.
  • Parents who already have a child with arginase deficiency still have a 1 in 4 chance of having another child with arginase 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.

• Poor growth (present in all the people who have arginase deficiency)
• Stiff muscles and increased reflexes (spasticity)
• Developmental delay
• Loss of previously acquired developmental milestones
• Intellectual disability
• Seizures
• Small head size (microcephaly)
• Problems with balance and coordination

A diagnosis of arginase deficiency is often suspected based on the person's signs and symptoms. Special blood tests to measure levels of arginine and ammonia may then be ordered. A diagnosis of arginase deficiency is confirmed when genetic testing identifies a disease-causing mutation in each copy of the ARG1 gene or a blood test demonstrates reduced arginase enzyme activity in the red blood cells.

In some cases, arginase deficiency in a newborn may be suspected if elevated levels of arginine are found through newborn screening.

Newborn screening for arginase deficiency is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much arginine is in your baby’s blood. Babies with high levels of arginine might have arginase deficiency.

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

If your baby’s blood spot screening result for arginase 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 are rare. Babies who receive supplemental nutrition (also called total parenteral nutrition [TPN] or hyperalimentation) may have out-of-range results.

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.