The condition is caused by a change in the HPD gene. This gene gives the body instructions for making the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). This enzyme helps break down the amino acid tyrosine.

When the HPD gene is changed, the body cannot break down enough tyrosine. As a result, tyrosine and related substances can build up and cause damage to the body.

Normal Function

The HPD gene provides instructions for making an enzyme called 4-hydroxyphenylpyruvate dioxygenase. This enzyme is abundant in the liver, and smaller amounts are found in the kidneys. It is second in a series of five enzymes that work to break down the amino acid tyrosine, a protein building block found in many foods. Specifically, 4-hydroxyphenylpyruvate dioxygenase converts a tyrosine byproduct called 4-hydroxyphenylpyruvate to homogentisic acid. Continuing the process, homogentisic acid is further broken down and ultimately smaller molecules are produced 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

Researchers have identified at least six HPD gene mutations that cause tyrosinemia type III. This condition is characterized by neurological problems such as intellectual disability, seizures, and periodic loss of balance and coordination (intermittent ataxia). Some of the mutations that cause this condition change single amino acids in the 4-hydroxyphenylpyruvate dioxygenase enzyme. Other mutations lead to the production of an unusually small enzyme. As a result of these mutations, the activity of the 4-hydroxyphenylpyruvate dioxygenase enzyme is unusually low or absent. As a result, the enzyme cannot perform its role in the breakdown of tyrosine, so 4-hydroxyphenylpyruvate is converted to toxic compounds instead of homogentisic acid. As these toxic compounds builds up in cells, they can impair function and eventually cause cell death. Cells in the nervous system are particularly sensitive to this toxic accumulation. Nerve cell damage and death likely lead to the characteristic features of tyrosinemia type III.

Other disorders

At least two HPD gene mutations have been found to cause a rare condition called hawkinsinuria. In infants, this condition is characterized by a failure to gain weight and grow at the expected rate (failure to thrive) and abnormally high acid levels in the blood (acidosis). The HPD gene mutations that cause hawkinsinuria result in decreased enzyme activity so that 4-hydroxyphenylpyruvate is not efficiently converted to homogentisic acid. Instead, some 4-hydroxyphenylpyruvate forms an unusual sulfur-containing amino acid called hawkinsin. It remains unclear how the production of hawkinsin leads to the features of hawkinsinuria.

Other Names for This Gene

• 4-HPPD
• 4HPPD
• GLOD3
• HPPD_HUMAN
• P-hydroxyphenylpyruvate hydroxylase
• P-hydroxyphenylpyruvate oxidase
• PPD

Genomic Location

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

• Tyrosinemia type III is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking HPD gene to their baby. Only babies with two nonworking HPD genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the HPD 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 HPD gene, they have a 1 in 4 chance of having a child with tyrosinemia type III.
  • Carriers for tyrosinemia type III 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 III.
  • Parents who already have a child with tyrosinemia type III still have a 1 in 4 chance of having another child with tyrosinemia type III. 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 III can vary greatly and are not well-known. 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.

Signs of the condition may include the following:

• Poor coordination and balance
• Seizures (epilepsy)

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

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

If your baby’s blood spot screening result for tyrosinemia type III 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 soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Babies who are born early (premature) may have out-of-range results. Also, babies with an immature liver, liver disease, or jaundice may have false-positive results.

In some cases, babies have temporary (transient) high levels of tyrosine that go away over time. This is called transient tyrosinemia of the newborn. It is a harmless condition and is not a lifelong genetic condition like tyrosinemia type I, II, and III.

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:

• Diet low in protein
• Special foods and formulas for children with tyrosinemia type III

Children who receive early and ongoing treatment for tyrosinemia type III can have healthy growth and development.