Home > Newborn Disorders > Tyrosinemia type 1
Tyrosinemia type 1
Screening
Tested By
tandem mass spectrometry (MS/MS); sensitivity~80% (with tyrosine), >99% with succinylacetone; specificity=99.98% [Schulze: 2003]Names
Tyrosinemia type 1
Hereditary tyrosinemia type 1 (HT1)
Hereditary infantile tyrosinemia
Hepatorenal tyrosinemia
Fumarylacetoacetase deficiency
Fumarylacetoacetate hydrolase deficiency (FAH deficiency)
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]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 on positive screening test
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): Utah Newborn Screening Program, (801-584-8256); See also Services below;
- For evaluation and ongoing collaborative management, consult the following service(s): Medical Genetics, (801-231-3599); See also Services below;
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 info 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 info for professionals (STAR-G)
On the Screening, Technology and Research in Genetics (STAR-G) site, one of a series of Disorder Fact Sheets for Professionals;
structured list of information about the condition, with links to more information.
ACT Sheet for Tyrosinemia type 1 (ACMG)
( 348 KB)
Developed by the American College of Medical Genetics (ACMG), includes recommended responses to positive newborn screening
test results, diagnostic evaluation, clinical expectations, and sources of additional information. See the ACMG ACT Sheets
and Confirmatory Algorithms (link elsewhere on this page) for more info and sheets on other conditions.
ACT Sheets and Confirmatory Algorithms (ACMG)
The American College of Medical Genetics (ACMG) has developed ACTion (ACT) Sheets and algorithms for responding to positive
newborn screening test results. This page contains a table with links to all of the ACT Sheets and related algorithms.
Tyrosinemia type 1, Emergency Protocol
A protocol for management of the patient with a positive screen for tyrosinemia type 1, from the New England Consortium of
Metabolic Programs.
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.
Resources for Tyrosinemia type 1 (NLM)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more; from the National
Library of Medicine and the Genetic Alliance.
Utah Newborn Screening Program
The site provides information and statistics about the program and related legislation, training for practices, and the conditions
screened for.
For Parents and Patients
Tyrosinemia type 1 info for parents (STAR-G)
From the Screening, Technology and Research in Genetics (STAR-G) site, providing information for parents about tyrosinemia
type 1 and links to other sites including parent support groups.
Tyrosinemia type 1 (Genetics Home Reference)
Excellent, detailed review aimed at patients and families from the National Library of Medicine's Genetics Home Reference
site.
National Urea Cycle Disorders Foundation
The National Urea Cycle Disorders Foundation, a non-profit organization, provides support services and information for families;
medical lectures on urea cycle disorders; nutrition and medication resources; and information about events and conferences.
Services
Newborn Screening Programs
Utah Newborn Screening Program,
more info...
44 Mario Capecchi Drive
Salt Lake City, UT 84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening
Pediatric Medical Genetics
See all Pediatric Medical Genetics services providers (3) in our database.
For other services related to this condition, browse our Services categories or search our database.
Helpful Articles
PubMed search for articles on tyrosinemia type 1 in the 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