Tyrosinemia Type 1

Other Names

Hereditary tyrosinemia type 1 (HT1)

Hereditary infantile tyrosinemia

Hepatorenal tyrosinemia

Fumarylacetoacetase deficiency

Fumarylacetoacetate hydrolase deficiency (FAH deficiency)

Diagnosis Coding

E70.21, tyrosinemia

Disorder Category

An amino acidemia

Screening

Finding

Elevated tyrosine; elevated succinylacetone

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.

Prevalence

About 1:125,000 live births [Schulze: 2003]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing, biochemical testing (succinylacetone) by amniocentesis.

Clinical Characteristics

With treatment, >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 prevent 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 is 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:
    • 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 that inhibits an enzyme (p—OH-phenylpyruvic acid dioxygenase) in the degardative pathway of tyrosine. Inhibition of this enzyme causes the immediate disappearance of succinylacetone. Renal Fanconi syndrome and rickects require treatment with activated vitamin D followed by standard vitamin D supplementation. Patients need repeated monitoring for the appearance of liver carncer with ultrasounds (MRI in suspsicious 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

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 transplation 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

Initial consultation and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Ongoing collaboration with gastroenterology and nephrology.

Resources

Information & Support

For Professionals

Tyrosinemia Type 1 - Information for Professionals (STAR-G)
Structured list of information about the condition and links to more information; Screening, Technology, and Research in Genetics.

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.

Newborn Screening Information for Clinicians (NNSGRC)
Fact sheets, data reports, publications ,and information for clinicians about genetic screening that includes links to state genetic contacts; National Newborn Screening & Global Resource Center.

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. Includes health supervision guidelines and other useful resources; a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Utah Newborn Screening Program (UDOH)
Provides information about the program, related legislation, training for practices, and newborn conditions; Utah Department of Health.

For Parents and Patients

Support

Utah Parent Center
A non-profit organization that provides training, information, referral, and assistance to parents of children and youth with all disabilities including physical, mental, hearing, vision, learning, behavioral, and emotional. Staff consists primarily of parents of children and youth with disabilities.

General

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)
Information from the genetics and rare diseases information center with links to additional information, Q and A, and investigational studies.

Center for Parent Information and Resources (DOE)
A large resource library related to children with disabilities. Parent Centers in every state provide training to parents of children with disabilities. Lists local conferences, support groups, advocacy tips, and suggestions for finding schools and other local services; Department of Education, Office of Special Education.

Tools

ACT Sheet for Tyrosinemia Type 1 (ACMG) (PDF Document 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

Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Newborn Screening Programs

See all Newborn Screening Programs services providers (3) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (5) 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.

Chace DH, Lim T, Hansen CR, De Jesus VR, Hannon WH.
Improved MS/MS analysis of succinylacetone extracted from dried blood spots when combined with amino acids and acylcarnitine butyl esters.
Clin Chim Acta. 2009;407(1-2):6-9. PubMed abstract / Full Text
The additional methanol wash steps did not alter SUAC assay results but did remove underivatized acylcarnitines which could result in the incorrect quantification of acylcarnitines.

Authors

Reviewing Author: Nicola Longo, MD, PhD - 7/2011
Compiled and edited by: Alfred Romeo, RN, PhD - 3/2007
Content Last Updated: 7/2011

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