The condition is caused by a change in the FAH gene. The FAH gene gives the body instructions for making the enzyme fumarylacetoacetate hydrolase (FAH). FAH helps break down the amino acid tyrosine.

Without a working FAH gene, FAH cannot break down enough tyrosine. As a result, tyrosine and related toxins like succinylacetone can build up and become toxic to their body.

Normal Function

The FAH gene provides instructions for making an enzyme called fumarylacetoacetate hydrolase. This enzyme is abundant in the liver and kidneys, and smaller amounts are found in many tissues throughout the body. Fumarylacetoacetate hydrolase is the last in a series of five enzymes that work to break down the amino acid tyrosine, a protein building block found in many foods. Specifically, fumarylacetoacetate hydrolase converts a tyrosine byproduct called fumarylacetoacetate into smaller molecules that are either excreted by the kidneys or used to produce energy or make other substances in the body.

Health Conditions Related to Genetic Changes

Tyrosinemia

At least 86 FAH mutations have been found that cause tyrosinemia type I. This condition is characterized by severe liver and kidney disease, neurological problems, and other signs and symptoms that begin in infancy. The altered FAH gene that causes this condition produces an unstable or inactive enzyme, which results in reduced or absent fumarylacetoacetate hydrolase activity. The most common FAH mutation disrupts the way the gene's instructions are used to make the enzyme. This mutation (written IVS12 + 5G>A) is called a splice-site mutation and results in an abnormally short enzyme. Without sufficient fumarylacetoacetate hydrolase activity, tyrosine and its byproducts are not properly broken down. As a result, fumarylacetoacetate accumulates in the liver and kidneys. Elevated levels of fumarylacetoacetate are thought to be toxic to cells and accumulation of this substance likely causes the liver and kidney problems and other features that are characteristic of tyrosinemia type I.

In several cases of tyrosinemia type I, the FAH gene mutation has been observed to revert to the normal state in some liver cells. If enough cells have the reverted gene, which produces normal fumarylacetoacetate hydrolase, some level of enzyme activity is achieved. Researchers have found a correlation between the severity of symptoms and the extent of reversion in liver cells. People with severe symptoms of tyrosinemia type I have few reverted cells, while those with milder symptoms have many cells with the reverted FAH gene.

Other Names for This Gene

• beta-diketonase
• FAA
• FAAA_HUMAN
• fumarylacetoacetase
• fumarylacetoacetate hydrolase (fumarylacetoacetase)

Genomic Location

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

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

Signs of tyrosinemia type I can vary widely, but typically develop within the first few months. These signs may be triggered by eating foods or milk that the body cannot break down or by going long periods without eating. The symptoms can also be caused by illnesses or infections. Milder forms of tyrosinemia type I may not appear until later in childhood or adulthood.

Signs of the condition may include the following:

• Poor growth or trouble gaining weight
• Diarrhea
• Vomiting
• Yellowing skin or eyes (jaundice)
• “Cabbage-like” odor
• Increased bleeding or bruising
• Trouble breathing

Newborn screening for tyrosinemia type I is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much tyrosine and succinylacetone are in your baby’s blood. Babies with high levels of tyrosine and succinylacetone might have tyrosinemia type I.

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

If your baby’s blood spot screening result for tyrosinemia 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 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 in the first few months of life if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. Typically, elevations of succinylacetone are only seen with tyrosinemia type I.

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.

There is currently no cure for tyrosinemia type 1. Individuals with this condition need to be on a special diet restricted in two amino acids, tyrosine and phenylalanine, throughout life. Affected individuals may also be treated with a medication called nitisinone. Treatment should start as soon as the condition is diagnosed. Some individuals require a liver transplant if their liver disease is already advanced before treatment begins.