Citrullinemia is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. Two types of citrullinemia have been described; they have different signs and symptoms and are caused by mutations in different genes.

Type I citrullinemia (also known as classic citrullinemia) usually becomes evident in the first few days of life. Affected infants typically appear normal at birth, but as ammonia builds up, they experience a progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. Some affected individuals develop serious liver problems. The health problems associated with type I citrullinemia are life-threatening in many cases. Less commonly, a milder form of type I citrullinemia can develop later in childhood or adulthood. This later-onset form is associated with intense headaches, blind spots (scotomas), problems with balance and muscle coordination (ataxia), and lethargy. Some people with gene mutations that cause type I citrullinemia never experience signs and symptoms of the disorder.

Type II citrullinemia chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. Affected individuals often have specific food preferences, preferring protein-rich and fatty foods and avoiding carbohydrate-rich foods. The signs and symptoms of this disorder typically appear during adulthood (adult-onset) and can be triggered by certain medications, infections, surgery, and alcohol intake. These signs and symptoms can be life-threatening in people with adult-onset type II citrullinemia.

Adult-onset type II citrullinemia may also develop in people who as infants had a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This liver condition is also known as neonatal-onset type II citrullinemia. NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly. In many cases, the signs and symptoms of NICCD go away within a year. In rare cases, affected individuals develop other signs and symptoms in early childhood after seeming to recover from NICCD, including delayed growth, extreme tiredness (fatigue), specific food preferences (mentioned above), and abnormal amounts of fats (lipids) in the blood (dyslipidemia). This condition is known as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Years or even decades later, some people with NICCD or FTTDCD develop the features of adult-onset type II citrullinemia.

The condition is caused by a change in the SLC25A13 gene. This gene gives your body instructions for making the protein citrin. Citrin helps break down sugars, make proteins, and get rid of toxins in your body.

Without a working SLC25A13 gene, your baby’s body cannot make citrin correctly. Their body cannot get rid of ammonia, which builds up in the body. They have trouble digesting foods that are high in carbohydrates, like bread or sugary treats. Their liver also has trouble working the way it should.

Normal Function

The SLC25A13 gene provides instructions for making a protein called citrin. This protein is active chiefly in the liver, kidneys, and heart. Within the cells of these organs, citrin is involved in transporting molecules into and out of energy-producing structures called mitochondria. Specifically, citrin carries a protein building block (amino acid) called glutamate into mitochondria and transports the amino acid aspartate out of mitochondria as part of a process called the malate-aspartate shuttle.

An adequate supply of aspartate must be transported out of mitochondria to participate in a process called the urea cycle. The urea cycle is a sequence of chemical reactions that takes place in liver cells. These reactions process excess nitrogen that is generated as the body uses proteins. The excess nitrogen is used to make a compound called urea, which is excreted from the body in urine.

Citrin participates in several other important cellular functions as part of the malate-aspartate shuttle. This protein plays a role in producing and breaking down simple sugars and making proteins. It is also involved in the production of nucleotides, which are the building blocks of DNA and its chemical cousin, RNA.

Health Conditions Related to Genetic Changes

Citrullinemia

More than 20 mutations in the SLC25A13 gene have been identified in people with adult-onset type II citrullinemia. This condition causes neurological problems, such as confusion, restlessness, irritability, and seizures, usually beginning in adulthood. Almost all of the identified mutations lead to the production of an unstable citrin protein that is quickly broken down or an abnormally short, nonfunctional version of the protein.

A lack of functional citrin blocks the malate-aspartate shuttle, including the transport of aspartate out of mitochondria. This loss of citrin inhibits the normal production of proteins and nucleotides. It also reduces the amount of aspartate available to take part in the urea cycle. As a result, the liver cannot effectively process excess nitrogen into urea. A disruption in the urea cycle allows nitrogen (in the form of ammonia) and other byproducts of the urea cycle (such as citrulline) to build up in the bloodstream. Ammonia is toxic, especially to the nervous system, which helps explain the development of abnormal behaviors and other neurological problems in people with adult-onset type II citrullinemia.

Mutations in the SLC25A13 gene also have been found in infants with a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This liver disorder is also known as neonatal-onset type II citrullinemia. NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly. Ammonia does not build up in the bloodstream of infants with NICCD, and the signs and symptoms typically go away within a year. In rare cases, these individuals develop signs and symptoms of another condition called failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) after recovering from NICCD. Many individuals with NICCD or FTTDCD have the same mutations in the SLC25A13 gene as people with adult-onset type II citrullinemia. Years or even decades later, some people who had NICCD or FTTDCD develop the features of adult-onset type II citrullinemia.

Other Names for This Gene

• ARALAR2
• calcium-binding mitochondrial carrier protein Aralar2
• CITRIN
• CMC2_HUMAN
• CTLN2
• mitochondrial aspartate glutamate carrier 2
• solute carrier family 25 (aspartate/glutamate carrier), member 13

Genomic Location

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

• Citrullinemia, type II is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking SLC25A13 gene to their baby. Only babies with two nonworking SLC25A13 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the SLC25A13 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 SLC25A13 gene, they have a 1 in 4 chance of having a child with citrullinemia, type II.
  • Carriers for citrullinemia, type II 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 II.
  • Parents who already have a child with citrullinemia, type II still have a 1 in 4 chance of having another child with citrullinemia, type II. 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 citrullinemia, type II can appear any time from birth to adulthood. Eating foods the body cannot break down properly, illness, infection, or a long time without food can all trigger citrullinemia, type II symptoms.

Signs of the condition may include the following:

• High levels of ammonia (hyperammonemia)
• Yellowish skin and eyes (jaundice)
• Liver problems (cholestasis)
• Delayed growth
• Extreme sleepiness or lack of energy (lethargy)
• Abnormal behavior (aggression, irritability, or hyperactivity)

Newborn screening for citrullinemia, type II 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 II.

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

If your baby’s blood spot screening result for citrullinemia, type II 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 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:

• Special formulas, vitamins, and supplements
• Low-carbohydrate diet
• Arginine supplements to lower ammonia levels
• Liver transplant

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

Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group.

This is similar to what is seen in sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. In addition, this condition has been most frequently reported in Japan and was initially described in that country, probably leading to a heightened clinical awareness not shared in the United States [and elsewhere]. Thus, the disorder could be significantly more common in other countries than originally believed.