The Pediatrician’s Guide to
Tyrosinemia Type I
What is tyrosinemia type I?
Tyrosinemia type I is a rare genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, resulting in severe liver disease.
Metabolic diseases are disorders that affect the body’s ability to perform certain chemical processes such as turning food into energy or recycling waste from dead cells. Many metabolic disorders do not have noticeable signs or symptoms at birth, but can eventually cause serious physical problems if not detected and treated early. There are several types of tyrosinemia (types I, II, and III, as well as a transient form that disappears spontaneously). This booklet describes type 1, which is the most severe form.
What symptoms are associated with tyrosinemia type I?
Symptoms associated with tyrosinemia type I often vary greatly from case to case. Infants with tyrosinemia type I typically present with either the acute or chronic form of the disorder.
The so-called acute form is present at birth or during the few first months of life. This form of the disorder is more common and severe than the chronic form. Infants with the acute form of tyrosinemia type I exhibit rapid onset of symptoms, usually beginning with failure to thrive. Additional early symptoms include:
Fever Diarrhea/bloody stools Vomiting Enlarged liver Tendency to bruise easily Jaundice Lethargy Irritability
Eventually, infants with the acute form of tyrosinemia type I experience:
Developmental delay Enlarged spleen Accumulation of fluid (edema) in the abdomen (ascites)
The disorder often rapidly progresses to acute life-threatening liver failure and blood clotting abnormalities (coagulopathy).
The chronic form of tyrosinemia type I occurs less frequently than the acute form and is characterized by a more gradual onset and less severe statement of the symptoms. Infants with the chronic form may eventually develop:
Progressive cirrhosis of the liver resulting in chronic liver failure Acute polyneuropathy Renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction, rickets, and episodes of vomiting, dehydration, weakness, and fever Hypertension Hypertrophic cardiomyopathy (heart muscle weakness) Hepatocellular carcinoma - Affected infants and children are at a greater risk than the general population to develop this form of liver cancer
How is tyrosinemia type I diagnosed?
A diagnosis of tyrosinemia type I is made based upon a thorough clinical evaluation and specialized tests. A diagnosis of tyrosinemia type I may be suspected in infants who display failure to thrive and enlarged liver during the first three months of life. Diagnosis may be confirmed through the detection of succinylacetone in the urine or decreased activity of the FAH enzyme in liver tissue or cultured fibroblasts.
Prenatal diagnosis of tyrosinemia type I is possible through detection of succinylacetone in the amniotic fluid or measurement of fumarylacetoacetase in amniotic fluid cells.
It is important to determine which type of tyrosinemia a child may have because other types are less severe than type I and are treated differently.
Are newborn screening tests available for tyrosinemia type I?
Most states have newborn screening programs that test infants for various metabolic disorders. However, states determine the number of disorders for which they will test. According to the American Academy of Pediatrics’ U.S. National Screening Status Report, July 2000, only two states (Georgia and Maryland) screen every newborn for tyrosinemia.
Why is early detection important?
Early detection of tyrosinemia is important because, in some cases, prompt identification and treatment (e.g., dietary restrictions) may prevent the development of serious problems during infancy. However, individuals may eventually require a liver transplant despite prompt treatment.
What causes tyrosinemia type I?
Tyrosinemia type I is inherited as an autosomal recessive trait. In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent. A child who receives one normal gene and one gene for the disease will be a carrier but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal for that trait. The risk is the same for each pregnancy.
The symptoms of tyrosinemia type I are caused by the accumulation of tyrosine and its metabolites (i.e., succinylacetoacetate, succinylacetone and fumarylacetone) in the liver.
Who gets tyrosinemia type I?
Tyrosinemia type I affects males and females in equal numbers. It is estimated to occur in one of every 100,000 births in the United States. In one region of the Quebec province of Canada, the disorder is estimated to occur in approximately one in 1,850 births.
Does tyrosinemia type I go by other names?
Tyrosinemia type I is also known as “hereditary infantile tyrosinemia” and “hepatorenal tyrosinemia”.
How is it treated?
Three main options exist for the treatment of tyrosinemia type I:
Diet
Infants with tyrosinemia type I should be placed on a low protein diet that contains limited amounts of phenylalanine and tyrosine. In some cases, affected infants have exhibited an improvement of liver and kidney abnormalities with dietary management alone. However, progression to cirrhosis, liver failure and potential liver cancer is still possible. Therefore, affected individuals must observe a very strict diet using special medical foods throughout their lifetime.
Liver transplant
Liver transplantation may be required in cases where affected infants develop end stage liver failure, or to prevent the potential development of liver cancer.
Investigational Medication
Favorable results have been reported regarding the investigational orphan drug nitisinone (Orfadin) as an experimental treatment for tyrosinemia type I. This drug is a protein inhibitor of 4-hydroxyphenylpyruvate dioxygenase that reduces the formation of toxic metabolites associated with tyrosinemia type I. It is produced by Rare Disease Therapeutics, Inc., and may be approved for marketing in the United States in 2001 or thereafter. Physicians wishing to obtain the drug while it remains experimental may contact the manufacturer at:
Rare Disease Therapeutics, Inc.
1101 Kermit Drive, Suite 608
Nashville, TN 37217
Tel: (615) 399-0700
Fax: (615) 399-1217
Genetic counseling will be of benefit for families of children with tyrosinemia.
*This pamphlet was funded by donors to the NORD/Danielle Barckett Tyrosinemia Research Fund.
