Robert Tomaino, Medical Writer
Tyrosinemia is a condition marked by the abnormal accumulation of an amino acid known as tyrosine in various organs of the body. Tyrosinemia is the main finding in a two separate, distinct disorders - tyrosinemia type I and tyrosinemia type II (Richner-Hanhart syndrome). Tyrosinemia type I is the most common, and potentially the most severe, form of tyrosinemia. Tyrosinemia type I and II are part of a larger group of disorders known as inborn errors of metabolism.
Tyrosinemia type I is a genetic disorder that results from a mutation in a gene, specifically the fumarylacetoacetase (FAH) gene. The FAH gene regulates the production of the enzyme fumarylacetoacetase, which is needed to metabolize (or breakdown) the amino acid tyrosine. Mutations of the FAH gene result in a deficiency of fumarylacetoacetase, which, in turn, results in a failure to breakdown tyrosine. The genetic mutation associated with tyrosinemia type I is inherited in an autosomal recessive manner.
The symptoms of tyrosinemia type I result from the abnormal accumulation of tyrosine or its metabolites in various organs of the body. Metabolites are substances that are normal byproducts of metabolism. Fumarylacetoacetate, maleylacetoacetate and succinylacetone are all normal byproducts of tyrosine metabolism that may be abnormally elevated in children with tyrosinemia type I.
Tyrosinemia type II is a genetic disorder that results from a mutation in the tyrosine aminotransferase (TAT) gene. The TAT gene regulates the production of tyrosine aminotransferase, which is an enzyme found only in liver cells (hepatocytes) and is required to breakdown tyrosine. Mutations of the TAT gene result in a deficiency of tyrosine aminotransferase, which, in turn, results in a failure to breakdown tyrosine. The genetic mutation associated with tyrosinemia type II is inherited in an autosomal recessive manner.
In the United States, the incidence of tyrosinemia type I is estimated to be 1 in 100,000 births. Fewer than 100 cases of tyrosinemia type II have appeared in the medical literature.
The specific symptoms and age of onset of tyrosinemia type I differ from one individual to another. The disorder is most common in the newborn period with the presenting symptom often failure to thrive. Infants may also be lethargic and irritable. Infants with tyrosinemia may develop some or all of the additional symptoms listed below:
- Enlarged liver
- Bloody stools
- Frequent and easy bruising
In some cases, symptoms may not become apparent until adolescence. In these cases, individuals often develop a less severe expression of symptoms.
Tyrosinemia type I is a progressive disorder. Additional symptoms will develop over time. These symptoms include developmental delays, an enlarged spleen, cirrhosis (scarring of the liver), and swelling of the stomach due to fluid retention. Eventually, tyrosinemia type I will cause life-threatening complications including liver or kidney failure and blood clotting deficiencies.
Additional symptoms may be associated with some cases of tyrosinemia type I including cardiomyopathy (heart muscle disease), peripheral neuropathy (damage to the peripheral nervous system), high blood pressure and bone disease secondary to renal tubular dysfunction (Fanconi syndrome). Children with tyrosinemia type I are at a greater risk of developing liver cancer than the general population.
The symptoms associated with tyrosinemia type II may affect the skin, eyes and central nervous system. Symptoms may include keratitis (inflammation of the cornea), palmoplantar hyperkeratosis (reddened, thickened skin on the hands and feet), and, potentially, mental retardation.
A diagnosis of tyrosinemia type I is suspected when urine or blood tests detect elevated levels of tyrosine and its metabolites. A liver biopsy may be used to detect decreased activity of the enzyme FAH in liver tissue and to determine overall liver function. A liver biopsy is a surgical procedure in which a needle is inserted through the ribs into the liver to obtain a tissue sample for microscopic study.
Prenatal diagnosis is possible through amniocentesis, a common prenatal procedure in which a small amount of amniotic fluid (the protective fluid that surrounds a fetus) is removed and studied. The presence of tyrosine and its metabolites in amniotic fluid is indicative of tyrosinemia. Decreased activity of FAH in amniotic fluid cells is also indicative of tyrosinemia.
A diagnosis of tyrosinemia type II is indicated when urine or blood tests detect elevated levels of tyrosine or its metabolites. A liver biopsy can confirm a diagnosis by revealing low levels of the enzyme tyrosine aminotransferase.
Treatment: The three main forms of treatment for tyrosinemia type I are adherence to a specialized diet, medication and liver transplantation. Diet and medication treat tyrosinemia type I by reducing or preventing the formation of tyrosine and its metabolites. A liver transplantation restores normal activity of the enzyme, fumarylacetoacetase.
- Diet - For years, tyrosinemia type I has been treated by a strict, low protein diet that has low levels of tyrosine and phenylalanine. Adherence to this diet may lead to an improvement of symptoms and slow the progression of the disorder. However, progression to serious complications such as liver failure may still occur.
- Medication - In January of 2002, the U.S. Food and Drug Administration (FDA) has approved the orphan drug nitisinone (Orfadin) for the treatment of tyrosinemia type I. The drug blocks the metabolism of tyrosine and reduces the accumulation of tyrosine and its metabolites in the body. The drug is used in conjunction with a low protein diet.
- Liver transplant - Some children may receive a liver transplant to treat end stage liver failure or as a preventative measure against the development of liver cancer. However, liver transplantation is considered a last resort in most cases because of the risk of morbidity or mortality associated with the procedure, the high cost, and the need of continued immunosuppressive therapy to prevent organ rejection.
The treatment for tyrosinemia type II usually involves a strict, low protein that limits the intake of tyrosine and phenylalanine. Adherence to this diet may lead to an improvement of symptoms and slow the progression of the disorder. Early detection of tyrosinemia type II is essential in order to prevent the development of mental retardation. Oral retinoids, which are drugs derived from vitamin A, may be used to treat skin conditions associated with this disorder.
Tyrosinemia types I and II are rare, serious disorders whose prognosis improves with early detection and prompt treatment. Greater familiarity and better recognition of these disorders in the medical community are essential to early diagnosis.
With the advent of new treatments, such as Orfadin, the quality of life and prognosis for children with tyrosinemia type I are improving. Clinical trials are currently underway to study additional new therapies for this rare disorder.
Less is known about tyrosinemia type II because of the limited number of cases reported in the medical journals. As more cases of this disorder are identified, a clearer clinical picture and new treatment theories should emerge.
Robert Tomaino is currently a freelance writer living in Danbury, CT. He graduated from the University of Richmond in 1994 with a degree in communications and journalism. Mr. Tomaino spent five years at the National Organization for Rare Disorders (NORD) where he started as a writer and became managing editor of the Information Services department. His responsibilities included writing and updating new and existing reports for NORD’s rare disease database, researching textbooks and medical databases for information on rare disorders, and developing working relationships with physicians across the country who are the leading experts concerning specific rare disorders. Mr. Tomaino also supervised a freelance writing team at NORD. After NORD, Mr. Tomaino worked at Enterprise Interactive, a business consulting firm, where he developed story ideas and researched various online sources for background information necessary to create news articles on topics related to e-commerce solutions, travel, and the Internet’s impact on business.