Other Names

Fumarylacetoacetase deficiency
Fumarylacetoacetate hydrolase deficiency (FAH deficiency)
Hepatorenal tyrosinemia
Hereditary infantile tyrosinemia
Hereditary tyrosinemia type 1
Tyrosinosis

Diagnosis Coding

Description

Most individuals with tyrosinemia type 1 present as infants with severe liver problems or later in life with liver and kidney problems, decreased growth, and rickets. Children with tyrosinemia type 1 also have neurologic crises and severe abdominal pain or other neurologic problems.

Click on the image to the left for a depiction of the metabolic pathway involved in the tyrosinemias (from the University of Florida Division of Genetics and Metabolism).

Tyrosinemia type 1 results from a deficiency of fumarylacetoacetate hydrolase, an enzyme responsible for the breakdown of the aromatic amino acid tyrosine. The metabolite succinylacetone accumulates, resulting in toxicity to liver and renal cells. Tyrosinemia type 1 is included in newborn bloodspot screening, identifying most affected infants when succinylacetone is used as primary marker. Patients can be missed when tyrosine is used as a marker, since levels can be normal in the newborn period in tyrosinemia type I. (See the Portal's Newborn Disorder page on Tyrosinemia Type 1.) Treatment prevents most of the toxicity resulting from the enzyme deficiency.

Prevalence

Prevalence estimates range from 1 in 250,000 births [Schulze: 2003] to 1 in 100,000 [Scriver: 2001]. These may underestimate the true incidence because, before newborn screening was implemented, many affected individuals were not diagnosed before death. The prevalence is higher in Norway and Quebec. Tyrosinemia type 1 (GeneReviews)

Genetics

Tyrosinemia type 1 is inherited in an autosomal recessive manner. Clinical testing for the gene responsible, fumarylacetoacetate hydrolase (FAH), is available. FAH gene testing (GTR)

Prognosis

If untreated, affected children typically die in childhood. Treatment prevents many of the effects of the condition, though there is a lifelong increased risk for the development of hepatocellular carcinoma and possibly lingering neuropsychological problems. [Schiff: 2011]

Roles Of The Medical Home

Medical Home clinicians provide ongoing primary care and collaborate with metabolic specialists to assure prompt referral and initiation of dietary and medical treatment following identification through newborn screening. Supporting the family in maintaining therapy and in obtaining insurance coverage for medication can be critical. Routine developmental screening and close monitoring for sequelae are important.

Practice Guidelines

Helpful Articles

Pubmed search for tyrosinemia type 1.

Scott CR.
The genetic tyrosinemias.
Am J Med Genet C Semin Med Genet. 2006;142C(2):121-6. PubMed abstract

Couce ML, Dalmau J, del Toro M, Pintos-Morell G, Aldámiz-Echevarría L.
Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.
Pediatr Int. 2011;53(6):985-9. PubMed abstract

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.

Overview

Most children will be diagnosed by newborn screening in the US, using succinylacetone as marker. Tyrosinemia type 1 should be suspected in any infant or child with liver disease or rickets. Even in treated children, hepatocellular carcinoma should be screened for at periodic intervals. Neuropsychological evaluation should be considered if the child has learning or attention problems. Episodes suggestive of neurologic crises should prompt evaluation of the amount of tyrosine restriction in the diet, nitisinone (NTBC) dosing, and/or compliance. Otherwise treated children should have a normal clinical course.

For The Condition

Newborn screening detects a high level of succinylacetone as a biomarker for tyrosinemia type. Tyrosinemia Type 1 [Morrissey: 2011]

Of Family Members

Children born to a family subsequent to the birth of a child with tyrosinemia should be screened immediately with blood and urine testing for succinylacetone to allow earliest possible treatment. Tyrosinemia type 1 (GeneReviews)

For Complications

Although the frequency is decreased in children treated with nitisinone, hepatocellular carcinoma must be screened for indefinitely with annual CTs of the abdomen, followed by MRIs if CT findings are suspicious. [Morrissey: 2011] [Schiff: 2011]

Presentations

Affected children may present:

1. as newborns – with severe liver involvement characterized with jaundice, ascites, loss of clotting factor synthesis, and GI bleeding
2. later in the first year with
   • liver involvement
   • renal involvement (renal tubular dysfunction)
   • growth failure
   • rickets
   • distinctive odor to the body and urine (boiled cabbage/rotten mushroom)
   • neurologic crises
3. as older children – with rickets and with only minimal liver involvement

Tyrosinemia type 1 (GeneReviews)

Differential Diagnosis

Tyrosine may also be elevated in tyrosinemia types II and III (caused by different metabolic defects), transient tyrosinemia of the newborn, liver disease, and a high protein diet. Liver abnormalities similar to those in infants with tyrosinemia type 1 may also be caused by:

• Infection (viral – CMV, hepatitis A/B, herpes, or bacterial – sepsis, salmonella, TB)
• Idiosyncratic drug reaction, acetaminophen toxicity, herbal medicine or mushroom poisoning
• Metabolic disorders, including Lowe syndrome, congenital disorders of glycosylation, transaldolase deficiency, cystinosis
• Any type of primary liver disease

Succinylacetone is elevated only in patients with tyrosinemia type I.

Comorbid Conditions

Neurologic crises, which occur in untreated children, are variable in presentation. A neuropathy with symptoms similar to Guillain-Barre syndrome, including diaphragmatic involvement with altered consciousness may be noted. Abdominal pain may accompany these crises, which may resemble an acute intermittent porphyria crisis. Crises may last 1 day to 1 week. Tyrosinemia type 1 (GeneReviews)

Pearls & Alerts

Newborn screening may miss the diagnosis

If tyrosine is used as the tested analyte. Tyrosine levels in newborns may be normal.

Neuropsychological abnormalities

may exist even in treated children. These should be monitored for with prompt treatment as necessary. [Schiff: 2011]

Neurologic crises may occur in treated children

who are not receiving adequate doses of nitinisone (NTBC) for whatever reason. [Schlump: 2008]

Family History

There will usually be no family history.

Current & Past Medical History

Assess adherence to dietary and treatment regimens. Be alert to symptoms that suggest neurologic involvement

Developmental & Educational Progress

Developmental and educational progress should be closely observed. [Schiff: 2011]

Social & Family Functioning

Some families may find it hard to be consistent with the phenylalanine/tyrosine-restricted diet and nitisinone dosing. This medicine may be quite expensive and may be difficult for families to afford.

Physical Exam

Newborn screening identifies most children with this condition. In children in whom this condition is suspected, and in newborn siblings of children already identified with this disorder, testing includes measurement of succinylacetone concentration in blood and urine.

Plasma amino acids (for tyrosine, and phenylalanine levels) and urine organic acids (for succinylacetone), alpha-fetoprotein, liver function tests levels, PT/PTT, and abdominal ultrasounds are followed regularly or as indicated clinically.

Genetic Testing

Testing for mutations in the gene that cause tyrosinemia type 1 (fumarylaceto-acetic acid hydrolase (FAH)) can be performed. See FAH gene testing (GTR).

Pearls & Alerts

Nitisinone, aka NTBC

(2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione), the drug used to treat tyrosinemia, has low toxicity but is expensive.

Systems

Funding & Access to Care

Writing Letters of Medical Necessity

Information for Clinicians

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.

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.

Resources for Tyrosinemia type 1 (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

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

Helpful Articles

Pubmed search for tyrosinemia type 1.

Couce ML, Dalmau J, del Toro M, Pintos-Morell G, Aldámiz-Echevarría L.
Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.
Pediatr Int. 2011;53(6):985-9. PubMed abstract

Scott CR.
The genetic tyrosinemias.
Am J Med Genet C Semin Med Genet. 2006;142C(2):121-6. PubMed abstract

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.

Information on the Web

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 (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

Tyrosinemia type 1 (GARD)
A summary of symptoms, diagnosis, treatment, and research; Genetics and Rare Diseases Information Center.

Support National & Local

National Urea Cycle Disorders Foundation
This 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.

Studies/Registries

Tyrosinemia Type 1 (ClinicalTrials.gov)
A list of clinical trials related to tyrosinemia type 1 that are registered with the National Institutes of Health.

Services for Patients & Families

For other services related to this condition, browse our Services categories or search our database.

Authors

Couce ML, Dalmau J, del Toro M, Pintos-Morell G, Aldámiz-Echevarría L.
Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.
Pediatr Int. 2011;53(6):985-9. PubMed abstract

El-Karaksy H, Fahmy M, El-Raziky M, El-Koofy N, El-Sayed R, Rashed MS, El-Kiki H, El-Hennawy A, Mohsen N.
Hereditary tyrosinemia type 1 from a single center in Egypt: clinical study of 22 cases.
World J Pediatr. 2011;7(3):224-31. PubMed abstract

El-Karaksy H, Rashed M, El-Sayed R, El-Raziky M, El-Koofy N, El-Hawary M, Al-Dirbashi O.
Clinical practice. NTBC therapy for tyrosinemia type 1: how much is enough?.
Eur J Pediatr. 2010;169(6):689-93. PubMed abstract

Morrissey MA, Sunny S, Fahim A, Lubowski C, Caggana M.
Newborn screening for Tyr-I: two years' experience of the New York State program.
Mol Genet Metab. 2011;103(2):191-2. PubMed abstract

Sander J, Janzen N, Terhardt M, Sander S, Gökcay G, Demirkol M, Ozer I, Peter M, Das AM.
Monitoring tyrosinaemia type I: Blood spot test for nitisinone (NTBC).
Clin Chim Acta. 2011;412(1-2):134-8. PubMed abstract

Santra S, Baumann U.
Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1.
Expert Opin Pharmacother. 2008;9(7):1229-36. PubMed abstract

Santra S, Preece MA, Hulton SA, McKiernan PJ.
Renal tubular function in children with tyrosinaemia type I treated with nitisinone.
J Inherit Metab Dis. 2008;31(3):399-402. PubMed abstract

Schiff M, Broue P, Chabrol B, De Laet C, Habes D, Mention K, Sarles J, Spraul A, Valayannopoulos V, Ogier de Baulny H.
Heterogeneity of follow-up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines.
J Inherit Metab Dis. 2011. PubMed abstract

Schlump JU, Perot C, Ketteler K, Schiff M, Mayatepek E, Wendel U, Spiekerkoetter U.
Severe neurological crisis in a patient with hereditary tyrosinaemia type I after interruption of NTBC treatment.
J Inherit Metab Dis. 2008;31 Suppl 2:S223-5. PubMed abstract

Schlune A, Thimm E, Herebian D, Spiekerkoetter U.
Single dose NTBC-treatment of hereditary tyrosinemia type I.
J Inherit Metab Dis. 2012. PubMed abstract

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

Scott CR.
The genetic tyrosinemias.
Am J Med Genet C Semin Med Genet. 2006;142C(2):121-6. PubMed abstract

Scriver CR, Beaudet AL, Sly WS, Valle D, eds. ed.
The Metabolic and Molecular Bases of Inherited Disease.
New York: McGraw Hill; 2001. 0079130356
Chapter on hypertyrosinemia by Mitchell GA, Grompe M, Lambert M, Tanguay RM.

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.