NORD gratefully acknowledges Kshitiz Singh, PhD, Research Fellow, The Children's Hospital of Philadelphia, and Robert M. Tanguay, DSc, Professor and Associate Head, Department of Molecular Biology, Medical Biochemistry & Pathology, Lab Cell & Developmental Genetics, Universite Laval, Quebec, Canada, for assistance in the preparation of this report.
Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocarcinoma if left untreated. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed.
Symptoms associated with tyrosinemia type I often vary greatly from person to person. Infants with tyrosinemia type I typically present with either the acute or chronic form of the disorder.
The acute form of tyrosinemia type I is present at birth (congenital) or during the first months of life. This form of the disorder is more common and severe than the chronic form. Infants with the acute form exhibit rapid onset of symptoms usually beginning with failure to gain weight and grow at the expected rate (failure to thrive). Additional early symptoms include fever, diarrhea, bloody stools (melena), and vomiting. Affected infants may also exhibit an abnormally enlarged liver (hepatomegaly), a tendency to bruise easily, jaundice, lethargy, and/or irritability. Some affected infants may develop a distinctive, cabbage-like odor.
Eventually infants with the acute form of tyrosinemia type I experience developmental delays, an abnormally enlarged spleen (splenomegaly), and accumulation of fluid (edema) in the abdomen (ascites). The disorder may 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 expression of the symptoms. Symptoms of tyrosinemia type I may not become apparent in infants with the chronic form of the disorder until after six months of age. Failure to thrive is often the first symptom. Additional symptoms include developmental delays and progressive scarring and impaired function (cirrhosis) of the liver resulting in chronic liver failure.
Many infants with tyrosinemia type I develop kidney (renal) abnormalities such as renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction that often leads to progressive softening and weakening of the bone structure (rickets). Fanconi syndrome is also associated with episodes of vomiting, dehydration, weakness, and fever.
Approximately 40 percent of affected infants also experience episodes of disease affecting many nerves (polyneuropathy) often following a minor infection. These episodes, which may be referred to as neurological crises, are associated with severe pains in the legs and stomach, increased muscle tone (hypertonia), vomiting, obstruction of the intestines (ileus), an irregular heartbeat (tachycardia), and high blood pressure (hypertension). Some affected individuals may also exhibit self-mutilating behavior (e.g., biting one’s tongue or grinding the teeth) during these episodes. Neurological crises and respiratory failure may occur.
Affected infants may also experience enlargement (hypertrophy) of the partition that separates the left and right ventricles of the heart and, in some children, of the left ventricular wall (hypertrophic cardiomyopathy). In addition, affected infants and children are at a greater risk than the general population to develop a form of liver cancer known as hepatocellular carcinoma.
Treatment of affected children with nitisinone and a low-tyrosine diet has improved survival to over 90% and resulted in normal growth, improved liver function, prevention of cirrhosis, correction of kidney disease and improvement in rickets.
Tyrosinemia is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene that is responsible for the production of the FAH enzyme. Deficiency of this enzyme leads to an accumulation of fumarylacetoacetate and accumulation of tyrosine and its metabolites in the liver, kidney, and central nervous system eventually causing tyrosinemia type I.
Tyrosinemia type I is inherited as an autosomal recessive genetic condition.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Tyrosinemia type I affects males and females in equal numbers. The prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. In Quebec, Canada, the birth prevalence is estimated to be 1/16,000. The estimated prevalence in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850 births. In Norway, the birth prevalence is estimated to be 1 in 60,000 births.
A diagnosis of tyrosinemia type I is made based upon a thorough clinical evaluation, a detailed patient history, and specialized tests. A diagnosis of tyrosinemia type I may be suspected in infants who display failure to thrive and an enlarged liver (hepatomegaly) during the first three months of life. The diagnosis is likely when tyrosine metabolites and succinylacetone are detected in the urine. It is also possible to make the diagnosis based on decreased activity of FAH in liver tissue or cultured fibroblasts, but this test is not readily available. Molecular genetic testing for FAH gene mutations is available to confirm the diagnosis.
Tyrosinemia type I may also be diagnosed through newborn screening programs. Succinylacetone can be measured on the newborn blood spot by tandem mass spectroscopy. Most states in the U.S. screen every newborn for tyrosinemia type 1. Early detection is important because prompt identification and treatment may prevent the development of serious problems during infancy.
Carrier testing and prenatal diagnosis by DNA analysis are available if the specific gene-causing mutation has been identified in the family. Next Generation DNA sequencing techniques, like exome sequencing, whole genome sequencing (WGS) can help in identifying the mutations responsible for the disease. Prenatal diagnosis is also possible by detection of succinylacetone and DNA analysis in amniotic fluid.
In 2017, Nityr (nitisinone tablets) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hereditary tyrosinemia type 1. Nityr is manufactured by Cycle Pharmaceuticals.
The FDA approved the orphan drug Orfadin, a capsule and oral suspension formulation of nitisinone, to treat tyrosinemia type I in 2002. Nitisinone was developed by Swedish Orphan International Biovitrum AB and is marketed by Sobi, Inc.
These drugs should only be prescribed by physicians experienced in treating tyrosinemia type I since the correct dose must be adjusted for each patient according to specific biochemical tests and to the weight. Access to a nutritionist skilled in managing children with inborn errors of metabolism requiring a low protein diet is an important part of therapy. Blood tests should be monitored regularly to maintain the correct dose for the patient.
Nitisinone must be used in conjunction with a diet restricted in the amino acids tyrosine and phenylalanine. Treatment with nitisinone and dietary management should begin as soon as possible after the diagnosis is confirmed.
Infants with tyrosinemia type I are placed on a low protein diet that contains limited amounts of phenylalanine and tyrosine. Some affected infants have exhibited an improvement of liver and kidney abnormalities with dietary management alone. However, progression to cirrhosis, liver failure and potential hepatocellular carcinoma is still possible. Physicians often recommend that affected individuals observe a strict diet using special medical foods throughout their lifetime.
Liver transplantation may be required for affected infants who have already developed end-stage liver failure by the time of diagnosis, have evidence of liver cancer (hepatocellular carcinoma), or do not respond to nitisinone therapy. In some children, liver transplantation improves kidney function.
Genetic counseling is recommended for affected individuals and their families. Other treatments are symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., liver disease, etc.)
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