Tyrosinemia

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at December 30, 2016
StartDiseasesTyrosinemia

Tyrosinemia is a genetic disorder in which the liver cannot break down tyrosine, an amino acid that is a component of most proteins. Tyrosinemia has three types, and each has its own unique set of symptoms. When tyrosinemia is left untreated, tyrosine and its byproducts build up in the body to toxic levels, leading to serious medical problems. With a proper diagnosis and treatment, most patients with tyrosinemia grow and develop normally. 

Contents

Definition & Facts

Tyrosinemia is a rare genetic condition in which the body lacks the enzymes necessary to break down tyrosine. When the body cannot break down tyrosine, too much of the amino acid and its metabolites accumulate in the body, causing serious medical issues.

There are three types of tyrosinemia, each with its own distinctive symptoms and genetic cause.

  • The most common form of the condition is tyrosinemia type I. It is estimated to affect one in 100,000 to 120,000 infants in the United States. The prevalence of the condition is higher in Norway, affecting approximately one in 60,000 infants. In one region in the Quebec province of Canada, tyrosinemia type I is estimated to affect one in 1,850 infants.
  • Tyrosinemia type II occurs in fewer than one in 250,000 people worldwide.
  • Tyrosinemia type III is the rarest type of tyrosinemia, with only a few cases having been reported thus far worldwide.

Symptoms & Complaints

Tyrosinemia type I has a multitude of symptoms. Symptoms tend to vary widely from person to person. Individuals with tyrosinemia type I usually present with either the acute or chronic form of the condition.

The acute form of the condition is present at birth or within the first few months of an infant's life. Symptoms tend to occur quickly, with failure to thrive typically being the initial noticeable symptom.

Other early symptoms of acute tyrosinemia type I include vomiting, bruising easily, irritability, diarrhea and bloody stool, an enlarged liver (hepatomegaly), and jaundice (yellowing of the skin and whites of the eyes which is also called the sclera). Some infants also have a distinctive cabbage-like odor.

As the disease progresses, an infant with the condition may experience blood clotting difficulties, which can result in gastrointestinal bleeding and frequent nosebleeds, an enlarged spleen (splenomegaly), kidney disease, developmental delays, and an accumulation of fluid in the abdomen. If the condition is left untreated, an infant can suffer life-threatening liver failure.

In the chronic form of tyrosinemia type I, symptoms tend to manifest gradually. Initial symptoms may include failure to thrive, an enlarged liver and spleen, vomiting, and diarrhea. As the condition progresses, an infant may experience developmental delays, progressive cirrhosis of the liver, which may result in chronic liver failure, and Fanconi syndrome. Fanconi syndrome is a rare condition characterized by softening of the bones (rickets), vomiting, weakness, fever, dehydration, and kidney dysfunction. 

Infants with tyrosinemia type I may also have repeated neurologic episodes (neurologic crises) that last from one to seven days. These episodes are characterized by abdominal pain, severe leg pain, respiratory failure, and altered mental status. Infants and children with tyrosinemia type I are also at greater risk of developing a certain type of liver cancer known as hepatocellular carcinoma

Tyrosinemia type II typically begins in early childhood. The condition is characterized by abnormal sensitivity to light (photophobia), eye redness and eye pain, tearing; thick and painful skin on the palms of the hands and soles of the feet; and intellectual disability. Tyrosinemia type III is characterized by periodic loss of coordination and loss of balance, intellectual disability, and seizures

Causes

Mutations in the FAH gene cause tyrosinemia type I. The FAH gene gives instructions to the fumarylacetoacetate hydrolase (FAH) enzyme, which is essential for the final stage of tyrosine breakdown in the liver. 

Mutations in the TAT gene are responsible for causing tyrosinemia type II. The TAT gene is responsible for producing the tyrosine aminotransferase enzyme, which is involved in the first step of tyrosine breakdown. 

Tyrosinemia type III is caused by mutations in the HPD gene. The HPD gene is responsible for giving instructions to the 4-hydroxyphenylpyruvate dioxygenase enzyme, which is involved in the second step of tyrosine breakdown.

All three types of tyrosinemia are autosomal recessive conditions, meaning a child must inherit a mutated gene from each parents in order to be affected by these conditions. 

Diagnosis & Tests

In the United States, most states now require all newborn babies to be screened for all three types of tyrosinemia. However, tyrosinemia is missed occasionally on these screening tests. When the screening tests miss tyrosinemia, a diagnosis is made based on a patient's medical history, family history, symptoms, and results from specialized tests.

Tyrosinemia type I may be suspected in infants who present with failure to thrive and an enlarged liver during their first three months of life. A diagnosis of this type of tyrosinemia can be confirmed through the presence of succinylacetone in the urine or decreased activity of the FAH enzyme in the liver tissue. Liver biopsies may reveal low levels of the tyrosine aminotransferase enzyme in individuals with tyrosinemia type II. 

Treatment & Therapy

Tyrosinemia type I is treated with medication and diet. The United States Food and Drug Administration approved nitisinone for the treatment of tyrosinemia type I. Nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, which decreases the toxic metabolites associated with tyrosinemia type I.

Infants with this condition must also consume a diet low in tyrosine and phenylalanine, both of which are found in meat and cheese. Infants and children who fail to respond to nitisinone, develop liver cancer, or develop end-stage liver failure may also need a liver transplant.

A diet low in tyrosine and phenylalanine is also utilized in the treatment of tyrosinemia type II. Quick resolution of skin and eye symptoms is usually seen once a patient begins the controlled diet. Oral retinoids may also be prescribed to treat the skin lesions associated with this condition. Patients diagnosed with tyrosinemia type III are likewise put on a diet restrictive in tyrosine and phenylalanine. 

Without treatment, tyrosinemia type I is usually fatal by the age of 10 due to liver cancer, liver failure, or neurological crisis. However, with proper diagnosis and treatment, tyrosinemia type I has a survival rate of greater than 90 percent. Children who receive early and ongoing treatment for tyrosinemia type II can grow and develop normally. Children who receive early treatment for tyrosinemia type III may never develop any signs of the condition.

Prevention & Prophylaxis

There is no way to prevent tyrosinemia. However, perspective parents can discuss their risk of passing on the mutated genes responsible for the condition with a genetic counselor. With genetic tests, a genetic counselor can determine if a perspective parent is a genetic carrier for one of the mutated genes responsible for causing tyrosinemia. 

Tyrosinemia is a rare genetic condition in which the body cannot break down tyrosine in the liver, leading to toxic levels of the amino acid in the blood. When this happens, serious medical issues can occur. Fortunately, with early treatment most individuals with tyrosinemia can live healthy lives.