Glutamate formiminotransferase deficiency is an inherited disorder that affects physical and mental development. There are two forms of this condition, which are distinguished by the severity of symptoms.

People with the mild form of glutamate formiminotransferase deficiency have minor delays in physical and mental development and may have mild intellectual disability. They also have unusually high levels of a molecule called formiminoglutamate (FIGLU) in their urine.

Individuals affected by the severe form of this disorder have profound intellectual disability and delayed development of motor skills such as sitting, standing, and walking. In addition to FIGLU in their urine, they have elevated amounts of certain B vitamins (called folates) in their blood.

The severe form of glutamate formiminotransferase deficiency is also characterized by megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The symptoms of this blood disorder may include decreased appetite, lack of energy, headaches, pale skin, and tingling or numbness in the hands and feet.

Mutations in the FTCD gene cause glutamate formiminotransferase deficiency. The FTCD gene provides instructions for making the enzyme formiminotransferase cyclodeaminase. This enzyme is involved in the last two steps in the breakdown (metabolism) of the amino acid histidine, a building block of most proteins. It also plays a role in producing one of several forms of the vitamin folate, which has many important functions in the body.

FTCD gene mutations that cause glutamate formiminotransferase deficiency reduce or eliminate the function of the enzyme. It is unclear how these changes are related to the specific health problems associated with the mild and severe forms of glutamate formiminotransferase deficiency, or why individuals are affected by one form or the other.

Normal Function

The FTCD gene provides instructions for making an enzyme called formiminotransferase cyclodeaminase. This enzyme is found mainly in the liver, with smaller amounts in the kidneys. In males it is also found in the testes.

Formiminotransferase cyclodeaminase is called a bifunctional enzyme because it performs two functions. Specifically, it is involved in the last two steps in the breakdown (metabolism) of the amino acid histidine, a building block of most proteins. It also plays a role in producing one of several forms of the vitamin folate, which has many important functions in the body.

One of the enzyme's functions, called formiminotransferase, breaks down a molecule called N-formiminoglutamate in the process of histidine metabolism. Part of the N-formiminoglutamate molecule, called the formimino group, is incorporated into another molecule called formiminotetrahydrofolate. The amino acid glutamate is also produced in this reaction.

The second function of the enzyme, called cyclodeaminase, breaks down formiminotetrahydrofolate to a molecule called 5,10-methenyltetrahydrofolate and ammonia. 5,10-methenyltetrahydrofolate is one of several tetrahydrofolate molecules involved in the production (synthesis) of many important molecules in the body, such as purines and pyrimidines (the building blocks of DNA and its chemical cousin, RNA) and amino acids. The tetrahydrofolates carry small molecules called one-carbon units that are needed for the synthesis of these larger molecules.

Health Conditions Related to Genetic Changes

Glutamate formiminotransferase deficiency

At least three FTCD gene mutations that cause glutamate formiminotransferase deficiency have been identified. Two of these mutations change an amino acid in the formiminotransferase cyclodeaminase enzyme sequence. These mutations reduce one of the enzyme's two activities, formiminotransferase. Another mutation results in the production of a formiminotransferase cyclodeaminase enzyme that is shortened so that the part of the enzyme that takes part in the cyclodeaminase reaction is missing. Disruption of these reactions results in the excretion of a molecule called formiminoglutamate (FIGLU) in the urine of affected individuals and, in some severe cases of glutamate formiminotransferase deficiency, a buildup of certain B vitamins called folates in the blood. It is unclear how the mutations result in the specific health problems associated with glutamate formiminotransferase deficiency.

Other Names for This Gene

• FTCD_HUMAN
• LCHC1

Genomic Location

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

• Glutamate formiminotransferase deficiency is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking FTCD gene to their baby. Only babies with two nonworking FTCD genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the FTCD 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 FTCD gene, they have a 1 in 4 chance of having a child with glutamate formiminotransferase deficiency.
  • Carriers for glutamate formiminotransferase 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 Glutamate formiminotransferase deficiency.
  • Parents who already have a child with glutamate formiminotransferase deficiency still have a 1 in 4 chance of having another child with glutamate formiminotransferase 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 and symptoms of glutamate formiminotransferase deficiency are not yet fully understood. Most babies and children with this condition will be well and have no signs or symptoms.

In rare cases, signs of the condition in children may include the following:

• Developmental delay
• Low levels of red blood cells (anemia)

Glutamate formiminotransferase deficiency may be detected by newborn screening. Newborn screening requires collecting a small amount of blood from your baby’s heel.

Screening measures how much of certain substances (called acylcarnitines) are in your baby’s blood. While looking at acylcarnitine levels, sometimes the substance formiminoglutamate (FIGLU) is also seen. FIGLU builds up when histidine cannot be completely broken down. Babies with high levels of FIGLU might have Glutamate formiminotransferase deficiency.

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

If your baby’s blood spot screening result for Glutamate formiminotransferase 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.

It is not currently known what might cause false-positive or false-negative newborn screening results for this condition.

Babies and children with glutamate formiminotransferase deficiency typically do not need any treatment.

If your baby does have signs and symptoms of glutamate formiminotransferase deficiency, it is important to talk to your health care provider about which treatment(s), if any, your baby needs.