Tyrosinemia Type 1
Other Names
Fumarylacetoacetase deficiency
Fumarylacetoacetate hydrolase deficiency (FAH deficiency)
Hereditary infantile tyrosinemia
Hepatorenal tyrosinemia
Hereditary tyrosinemia type 1 (HT1)
Screening
Tested By
Tandem mass spectrometry (MS/MS); sensitivity~80% (with tyrosine), >99% with succinylacetone; specificity=99.98% [Schulze: 2003]Overview
Tyrosinemia type I is caused by a deficiency of fumarylacetoacetase (FAH), one of the last enzymes in aromatic amino acid metabolism. This results in a mild increase in plasma tyrosine (that can be missed by newborn screening) and the accumulation of succinylacetone (that is specific for this condition) and related compounds that are extremely toxic. These compounds are produced in the liver and kidney resulting in liver failure, cirrhosis, and development of liver cancer. Patients can also present with failure to thrive and rickets due to severe renal tubular dysfunction.Incidence
About 1:125,000 live births [Schulze: 2003]Clinical Characteristics
With treatment, a >90% survival rate can be expected, along with normal growth, normalization of liver function and prevention of cirrhosis, correction of renal tubular acidosis, and resolution of secondary rickets. Early treatment is associated with reduced incidence of hepatic cancer. Treatment consists of a diet low in tyrosine and phenylalanine and use of a drug (nitisone or NTBC) that prevents formation of succinylacetone, the toxic agent responsible for liver and kidney damage. Patients with evidence of cirrhosis or liver cancer require liver transplantation. Without treatment, chronic problems ensue, including liver disease leading to cirrhosis and hepatocellular carcinoma, renal tubular disease (Fanconi syndrome), rickets, failure to thrive, and coagulation disorders. Repeated neurologic crises may occur involving mental status change, abdominal pain, peripheral neuropathy, and/or respiratory failure. These are due to the accumulation of delta amino levulinic acid, whose metabolism inhibited by succinylacetone. Death usually occurs by 10 years of age.Initial symptoms may include:
- Severe liver involvement in the young infant with:
- Jaundice
- Ascites
- Loss of clotting factor synthesis
- GI bleeding
- Or development later in the first year of life:
- Liver dysfunction
- Renal involvement
- Growth failure
- Rickets
- "Boiled cabbage" or "rotten mushroom" odor to the body and urine
Treatment consists of a diet low in tyrosine and phenylalanine and therapy with the orphan drug NTBC (aka nitisinone) that inhibits an enzyme (p—OH-phenylpyruvic acid dioxygenase) in the degradative pathway of tyrosine. Inhibition of this enzyme causes the immediate disappearance of succinylacetone. Renal Fanconi syndrome and rickets require treatment with activated vitamin D followed by standard vitamin D supplementation. Patients need repeated monitoring for the appearance of liver cancer with ultrasounds (MRI in suspicious cases) and alpha-fetoprotein levels.
Follow-up Testing after Positive Screen
Quantitative plasma amino acid analysis, urine organic acid analysis. DNA testing needs to be obtained for definitive diagnostic confirmation.Primary Care Management
Upon Notification of the + Screen
- Contact the family and evaluate the infant for evidence of liver disease (though most neonates will be asymptomatic).
- Provide emergency treatment/referral for jaundice, bloody stools, or seizures (see the ACT Sheet for Tyrosinemia Type 1 (ACMG) (
348 KB) for additional information).
- To confirm the diagnosis, work with the following service(s): see all Newborn Screening Programs services providers (3) in our database.
- For evaluation and ongoing collaborative management, consult the following service(s): see all Pediatric Genetics services providers (6) in our database.
If the Diagnosis is Confirmed
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Tyrosinemia Type 1 - Information for Parents (STAR-G)).
- Support initiation and maintenance of dietary restriction of phenylalanine and tyrosine.
- Treatment with Nitisinone [NTBC or 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione)], a competitive inhibitor of an upstream enzyme that reduces the production of toxic metabolites.
- Vitamin D supplements may be indicated for affected children.
- Regular blood and urine tests to monitor amino acid, succinylacetone, and alpha-fetoprotein levels; kidney and liver function; and diet may be indicated.
- CT or MRI liver scans for early diagnosis of scarring or cancer may be indicated.
- Liver transplantation may be considered to prevent hepatocellular carcinoma.
- For those identified after irreversible sequelae, assist in management of liver and kidney disease and support with developmental and educational interventions.
Specialty Care Collaboration
Initiate consultation and ongoing collaboration with gastroenterology and nephrology if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management.Resources
Information & Support
For Professionals
Tyrosinemia type 1 (GeneReviews)
Excellent review by Lisa Sniderman King, Cristine Trahms, and C. Ronald Scott, including clinical description, differential,
management, genetic counseling, molecular genetics, and a bibliography; U.S. National Library of Medicine.
Resources for Tyrosinemia type 1 (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.
Tyrosinemia Type 1 (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man
site, hosted by Johns Hopkins University.
Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes
health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services
Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.
For Parents and Patients
Tyrosinemia Type 1 (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.
Tyrosinemia Type 1 - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received
an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.
Tyrosinemia type 1 (GARD)
A summary of symptoms, diagnosis, treatment, and research; Genetics and Rare Diseases Information Center.
Center for Parent Information and Resources (DOE)
Maintains a large resource library with information related to children with disabilities. Parent Centers in every state provide
training to parents of children with disabilities and provide information about local conferences, support groups, and finding
schools and other local services; Department of Education, Office of Special Education.
Practice Guidelines
Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein
MP, Coakley K, Scott CR.
Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.
Genet Med.
2017;19(12).
PubMed abstract / Full Text
Tools
ACT Sheet for Tyrosinemia Type 1 (ACMG) ( 348 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
Confirmatory Algorithms Tyrosinemia Elevated SUAC Normal (ACMG)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American
College of Medical Genetics.
Confirmatory Algorithms Tyrosinemia Normal or Elevated SUAC Elevated (ACMG)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American
College of Medical Genetics.
Services
Newborn Screening Programs
See all Newborn Screening Programs services providers (3) in our database.
For other services related to this condition, browse our Services categories or search our database.
Studies
Tyrosinemia Type 1 (ClinicalTrials.gov)
A list of clinical trials related to tyrosinemia type 1 that are registered with the National Institutes of Health.
Helpful Articles
PubMed search for tyrosinemia type 1 and neonatal screening, last 5 years.
de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, de Baulny HO, Pintos-Morell G, Spiekerkötter U.
Recommendations for the management of tyrosinaemia type 1.
Orphanet J Rare Dis.
2013;8:8.
PubMed abstract / Full Text
Developed by a European collaboration; recommendations may not apply to the United States, particularly as they relate to
early diagnosis, since tyrosinemia is now routinely screened for in the US.
McKiernan PJ, Preece MA, Chakrapani A.
Outcome of children with hereditary tyrosinaemia following newborn screening.
Arch Dis Child.
2015;100(8):738-41.
PubMed abstract
Page Bibliography
Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome,
and implications.
Pediatrics.
2003;111(6 Pt 1):1399-406.
PubMed abstract