Montana Medical Home Portal - Tyrosinemia Type 1

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Fumarylacetoacetase deficiency
Fumarylacetoacetate hydrolase deficiency (FAH deficiency)
Hereditary infantile tyrosinemia
Hepatorenal tyrosinemia
Hereditary tyrosinemia type 1 (HT1)

ICD-10 Coding

E70.21, Tyrosinemia

Disorder Category

Amino acidemia

Screening

Abnormal Finding

Elevated tyrosine; elevated succinylacetone

Tested By

Tandem mass spectrometry (MS/MS); sensitivity~80% (with tyrosine), >99% with succinylacetone; specificity=99.98% [Schulze: 2003]

Prenatal Testing

DNA testing, biochemical testing (succinylacetone) by amniocentesis

Description

Tyrosine Catabolic Pathway

Tyrosinemia Type I Catabolic Pathway Mutation and Action of Drug

Inherited defects in tyrosine metabolism cause the failure of tyrosine (derived from dietary protein) to convert to other compounds necessary for metabolism. 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 (pathognomonic for tyrosinemia type 1).

With time, elevated succinylacetone and related toxic compounds produced in the liver and kidneys will cause liver and renal dysfunction, failure to thrive, rickets due to severe renal tubular dysfunction, and high risk for developing hepatocellular carcinoma. This most severe form is usually asymptomatic in the neonate.

Clinical Characteristics

With treatment of tyrosinemia type 1, a >90% survival rate can be expected, along with normal growth, normalization of liver function, correction of renal tubular acidosis, and resolution of secondary rickets. Early treatment is also associated with a significantly reduced risk of hepatocellular carcinoma.

Treatment consists of a diet low in the protein-derived amino acids tyrosine and phenylalanine, and nitisinone (NTBC), a medication that inhibits upstream tyrosine degradation, thereby preventing the formation of succinylacetone. Patients unresponsive to nitisinone or with severe liver disease may still 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 involve mental status change, abdominal pain, peripheral neuropathy, and/or respiratory failure. These are due to the accumulation of delta-aminolevulinic acid, whose metabolism is inhibited by succinylacetone. Death usually occurs by 10 years of age.

Initial symptoms of tyrosinemia type 1 may include:

Severe liver involvement in the young infant with:
- Jaundice
- Ascites
- Coagulopathy
- 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

Incidence

Globally, the prevalence of tyrosinemia type 1 is 1:100,000 newborns but higher in Quebec, Canada, where its prevalence is 1:1846. [Fuenzalida: 2021] In the US, the estimated prevalence is 1:780,000, although this is based on newborn screening programs, many of which only measure tyrosine levels, suggesting the possibility of missed cases. [Therrell: 2014]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

Contact the family and evaluate the infant for evidence of liver disease, jaundice, diarrhea, or vomiting (although most neonates will be asymptomatic).
Provide emergency treatment/referral for jaundice, bloody stools, or seizures. See the ACT Sheet for Tyrosinemia (ACMG) ( 348 KB).

Confirming the Diagnosis

To confirm the diagnosis, work with Newborn Screening Services (see MT providers [4]).
Quantitative plasma amino acid analysis, urine organic acid analysis. Quantitative succinyl acetone may be advised to differentiate from the other forms of tyrosinemia if not included in the newborn screening process. Molecular genetic testing may need to be obtained to confirm the diagnosis.

If the Diagnosis is Confirmed

For evaluation and ongoing collaborative management, consult Medical Genetics (see MT providers [8]).
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.
Vitamin D supplements may be indicated for affected children. See Calcium and Vitamin D.
Regular blood and urine tests to monitor amino acid, succinylacetone, and alpha-fetoprotein levels; kidney and liver function; and diet may be indicated.
Abdominal ultrasounds are performed on a regular basis, with an MRI of the liver performed when there are suspicious lesions.
For those identified after irreversible sequelae, assist in management of liver and kidney disease and support with developmental and educational interventions. Refer infants at risk for developmental delays for assessment and support to Early Intervention for Children with Disabilities/Delays (see MT providers [27]).
Initiate consultation and ongoing collaboration with gastroenterology and nephrology if the child is affected.
Nutrition, Metabolic (see MT providers [17]) may work with the family to devise an optimal approach to dietary management.
Refer the family to Genetic Testing and Counseling (see MT providers [13]).

Resources

Information & Support

Related Portal Content
Tyrosinemia Type 1
Assessment and management information for the primary care clinician caring for the child with Tyrosinemia Type 1.

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Tyrosinemia Type 1 (GeneReviews)
Clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Tyrosinemia Type 1 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man.

Newborn Screening (HRSA)
Detailed information about the newborn screening process by state and condition; Health Resources & Services Administration.

Tyrosinemia (Canadian Liver Foundation)
Cause, symptoms, diagnosis, and treatment information.

For Parents and Patients

Support

Tyrosinemia Society
Includes advocates, caregivers, and health professionals in order to provide education and encouragement to families living with tyrosinemia. Includes a link to a Facebook support group for tyrosinemia.

Center for Parent Information and Resources (DOE)
Parent Centers in every state provide training to parents of children with disabilities and provide information about special education, transition to adulthood, health care, support groups, local conferences, and other federal, state, and local services. See the "Find Your Parent Center Link" to find the parent center in your state; Department of Education, Office of Special Education.

Cook For Love
Offers a collection of delicious low-protein recipes from a chef and mother of a child with PKU. A free membership is required to access the content.

General

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)
Includes information about symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations; Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.

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

MT ACT Sheet for Tyrosinemia (ACMG) ( PDF Document 123 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Confirmatory Algorithm for Tyrosinemia (ACMG) ( PDF Document 146 KB)
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 for Patients & Families in Montana (MT)

Service Categories	MT	NW		NM	NV	RI
Early Intervention for Children with Disabilities/Delays	27	3	44	32	14	55
Genetic Testing and Counseling	13	7	7	14	9	14
Medical Genetics	8	1	4	5	4	6
Medical Genetics Clinics	7	1	1	2	1	3
Newborn Screening Services	4	1	1	2	2	3
Nutrition, Metabolic	17	15	15	16	17	16

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Studies

Tyrosinemia Type 1 (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Helpful Articles

PubMed search for tyrosinemia type 1 and neonatal screening, last 10 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

van Ginkel WG, Rodenburg IL, Harding CO, Hollak CEM, Heiner-Fokkema MR, van Spronsen FJ.
Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1.
Paediatr Drugs. 2019;21(6):413-426. PubMed abstract / Full Text

Pass K, Morrissey M.
Clinical Chemistry: Enhancing Newborn Screening for Tyrosinemia Type I.
Volume 54, Issue 4 ed. pp. 627–629: Oxford Academic; 2008. https://academic.oup.com/clinchem/article/54/4/627/5628481

Authors & Reviewers

Initial publication: March 2007; last update/revision: April 2022

Current Authors and Reviewers:

Authors:	Hannah Holik
	Kimberly Stowers, MD
Senior Author:	Brian J. Shayota, MD, MPH
Reviewer:	Nancy C. Rose, MD

Authoring history

2018: update: Nicola Longo, MD, Ph.D.^A

2011: first version: Nicola Longo, MD, Ph.D.^A

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

Page Bibliography

Fuenzalida K, Leal-Witt MJ, Guerrero P, Hamilton V, Salazar MF, Peñaloza F, Arias C, Cornejo V.
NTBC Treatment Monitoring in Chilean Patients with Tyrosinemia Type 1 and Its Association with Biochemical Parameters and Liver Biomarkers.
J Clin Med. 2021;10(24). PubMed abstract / Full Text

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

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text