Tyrosinemia is a genetic disorder characterized by problems breaking down the amino acid tyrosine, which is a building block of most proteins. If the condition is untreated, tyrosine and its byproducts build up in tissues and organs, which can lead to serious health problems.

There are three types of tyrosinemia, distinguished by their symptoms and genetic cause. Tyrosinemia type I is the most severe form of this disorder and usually begins in the first few months of life. Affected infants do not gain weight and grow at the expected rate (failure to thrive) because eating high-protein foods leads to diarrhea and vomiting. Affected infants may also have yellowing of the skin and whites of the eyes (jaundice), a cabbage-like odor, and an increased tendency to bleed (particularly nosebleeds).

In addition, tyrosinemia type I can lead to liver and kidney failure, softening and weakening of the bones (rickets), and an increased risk of liver cancer (hepatocellular carcinoma). Some affected children have repeated neurologic crises that consist of changes in their mental state, reduced sensation in the arms and legs (peripheral neuropathy), abdominal pain, and serious breathing problems (respiratory failure). These crises can last from 1 to 7 days. Without treatment, children with tyrosinemia type I often do not survive past the age of 10. With early diagnosis and treatment, though, affected individuals can live into adulthood.

Tyrosinemia type II often begins in early childhood and affects the eyes, skin, and mental development. Signs and symptoms include eye pain and redness, excessive tearing, abnormal sensitivity to light (photophobia), and thick, painful skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis). About half of individuals with tyrosinemia type II have some degree of intellectual disability.

Tyrosinemia type III is the rarest of the three types. The characteristic features of this type include intellectual disabilities, seizures, and periodic loss of balance and coordination (intermittent ataxia). Liver problems do not occur in types II and III.

About 1 in 10 of all newborns have temporarily elevated levels of tyrosine (transient tyrosinemia). These cases are not genetic. The most likely causes are vitamin C deficiency or an immature liver due to premature birth.

Variants (also called mutations) in the FAH, TAT, and HPD genes can cause tyrosinemia types I, II, and III, respectively.

In the liver, specialized proteins called enzymes break down tyrosine in a five-step process. The resulting molecules are either removed from the body by the kidneys or used in the body to produce energy or make other substances.

The FAH gene provides instructions for making an enzyme called fumarylacetoacetate hydrolase, which performs the last step of tyrosine breakdown. The enzyme produced from the TAT gene, called tyrosine aminotransferase enzyme, is involved in the first step in the process. The HPD gene provides instructions for making the 4-hydroxyphenylpyruvate dioxygenase enzyme, which performs the second step.

Variants in the FAH, TAT, or HPD gene reduce the activity of one of the enzymes that break down tyrosine. As a result, tyrosine and its byproducts accumulate to toxic levels, which can damage and kill cells in the liver, kidneys, nervous system, and other organs.

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

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

Normal Function

The TAT gene provides instructions for making a liver enzyme called tyrosine aminotransferase. This enzyme is the first in a series of five enzymes that work to break down the amino acid tyrosine, a protein building block found in many foods. Specifically, tyrosine aminotransferase converts tyrosine into a byproduct called 4-hydroxyphenylpyruvate. Continuing the process, 4-hydroxyphenylpyruvate 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

At least 22 TAT gene mutations have been found to cause tyrosinemia type II. This condition often affects the eyes, skin, and mental development. Most of these mutations change single DNA building blocks (base pairs) within the TAT gene. Research suggests that the altered TAT gene produces a tyrosine aminotransferase enzyme with reduced activity. Other mutations delete all or part of the TAT gene, eliminating enzyme activity. As a result of these mutations, tyrosine is not properly broken down. Tyrosine levels are elevated and some tyrosine is converted into other molecules that may be toxic to cells. It is unclear how impaired break down of tyrosine leads to the skin, eye, and intellectual problems that characterize tyrosinemia type II.

Other Names for This Gene

• ATTY_HUMAN
• L-tyrosine:2-oxoglutarate aminotransferase
• tyrosine transaminase

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Worldwide, tyrosinemia type I affects about 1 in 100,000 individuals. This type is more common in Norway, where 1 in 60,000 to 74,000 individuals are affected, and Quebec, Canada, where it occurs in about 1 in 16,000 individuals. It is especially common in the Saguenay-Lac St. Jean region of Quebec, where it affects 1 in 1,846 people.

Tyrosinemia type II occurs in fewer than 1 in 250,000 individuals worldwide.

Tyrosinemia type III is very rare; only a few cases have been reported.