Clinical characteristics.

Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Newborn screening / early diagnosis and combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.

Diagnosis/testing.

The diagnosis of tyrosinemia type I can be established in a proband by identification of increased succinylacetone concentration in the blood and urine or biallelic pathogenic variants in FAH by molecular genetic testing.

Management.

Targeted therapies: Nitisinone; low-phenylalanine, low-tyrosine diet; liver transplantation for children with severe liver failure at presentation and failure to respond to nitisinone therapy or malignant changes in hepatic tissue.

Supportive care: Additional treatment (especially for those not receiving nitisinone) includes: antihypertensive medications and/or referral to nephrologist for management of hypertension; correction of metabolic acidosis, restoring calcium and phosphate balance, and 25-hydroxyvitamin D supplementation for osteoporosis/rickets; management of liver disease per hepatologist; treatment of hepatocellular carcinoma per oncologist/hepatologist; nutrition support per metabolic dietician; frequent feeds and avoidance of fasting to prevent hypoglycemia; developmental services and educational support as needed; provide written protocols and letters for emergency management; transitional care plan. Acute inpatient treatment for neurologic crises includes intravenous glucose, antihypertensives, analgesics, correction of hyponatremia, and prompt nitisinone therapy, with crises prevented by strict long-term adherence and monitoring.

Surveillance: Plasma concentrations of methionine, phenylalanine, and tyrosine, blood and urine succinylacetone concentrations, blood nitisinone concentration, complete blood count, serum alpha-fetoprotein, routine coagulation tests, liver enzymes, and bilirubin concentrations should be measured per age-related recommendations. Liver imaging annually or as clinically indicated to assess for hepatocellular carcinoma. Blood urea nitrogen and creatinine, urine phosphate, calcium, and protein-to-creatinine ratio, and kidney ultrasound as clinically indicated to evaluate for kidney disease. Wrist radiographs as clinically indicated to evaluate for rickets. Developmental assessment at each visit or as clinically indicated. Neuropsychological testing should be done before school age and then as indicated. Assess for ophthalmologic manifestations at each visit with slit lamp examination if symptomatic. Psychosocial assessment at each visit or as clinically indicated.

Agents/circumstances to avoid: Excessive dietary protein or protein malnutrition inducing catabolic state; prolonged fasting; catabolic illness (intercurrent infection, brief febrile illness post vaccination); inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia).

Evaluation of relatives at risk: Testing of at-risk sibs of any age is warranted to allow for early diagnosis and prompt initiation of treatment. Prenatal testing (if the familial FAH pathogenic variants are known) may be performed via amniocentesis or chorionic villus sampling. If prenatal testing was not performed, then – in parallel with NBS – urine and blood succinylacetone should be analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy (FAH molecular genetic testing can be performed if the familial pathogenic variants are known).

Pregnancy management: Limited data exist on the use of nitisinone during human pregnancy; however, at least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone.

Genetic counseling.

Tyrosinemia type I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FAH pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FAH pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for tyrosinemia type I are possible.

Suggestive Findings

Tyrosinemia type I should be suspected in:

• An infant with an out-of-range newborn screening (NBS) result;
• An individual at any age with clinical and biochemical findings suggestive of tyrosinemia type I (including late-onset tyrosinemia type I).

Establishing the Diagnosis

Clinical Description

Tyrosinemia type I is characterized by progressive liver disease, renal tubular dysfunction, and an increased risk of neurologic crises and hepatocellular carcinoma resulting from the accumulation of toxic metabolites due to a deficiency of fumarylacetoacetate hydrolase (FAH).

For children not detected by newborn screening (NBS), tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and significant kidney involvement, growth failure, and rickets. Death in the undetected or untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma.

• Liver involvement. Undetected or untreated children presenting before age six months typically have acute liver failure with initial loss of synthetic function for clotting factors. Prothrombin time and partial thromboplastin time (PTT) are markedly prolonged and not corrected by vitamin K supplementation; factor II, VII, IX, XI, and XII levels are decreased; factor V and factor VIII levels are preserved. Paradoxically, serum transaminase levels may be only modestly elevated. Serum bilirubin concentration may be normal or only slightly elevated, in contrast to most forms of severe liver disease in which marked elevation of transaminases and serum bilirubin concentration occur concomitantly with prolongation of prothrombin time and PTT. Resistance of affected liver cells to cell death may explain the observed discrepancy in liver function [Vogel et al 2004].
  This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [Baumann et al 2005]. Others have chronic low-grade acidosis. Untreated affected infants may die from liver failure within weeks or months of first manifestations [Hegarty et al 2015].
• Proximal renal tubular involvement. In the more chronic form of untreated tyrosinemia type I, manifestations develop after age six months; renal tubular involvement is the major manifestation. The renal tubular dysfunction involves a Fanconi-like renal syndrome with generalized aminoaciduria, phosphate loss, and, for many, renal tubular acidosis. The continued renal loss of phosphate is believed to account for rickets; serum calcium concentrations are usually normal. Proximal tubular dysfunction can lead to chronic kidney disease and hypertension.
• Growth failure is a common and early feature of untreated tyrosinemia type I. Poor weight gain and growth deficiency result from chronic illness with poor nutritional intake, liver involvement, and/or chronic kidney disease.
• Neurologic crises. Untreated children may have repeated neurologic crises similar to those seen in older individuals with acute intermittent porphyria. These crises include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Crises can last one to seven days. Repeated neurologic crises often go unrecognized. Mitchell et al [1990] reported that 42% of untreated French Canadian children with tyrosinemia type I had experienced such episodes. In an international survey, 10% of deaths in untreated children occurred during a neurologic crisis [van Spronsen et al 1994].
• Developmental delay and intellectual disability in individuals with tyrosinemia type I is most often identified in infancy or early childhood, especially if diagnosis or treatment is delayed. Some individuals have mild delays; others have intellectual disability, with executive function and attention often affected. Developmental regression can occur, particularly in children with early, severe disease and delayed treatment, but regression is not universal [De Laet et al 2011, Thimm et al 2012, Bendadi et al 2014, García et al 2017, Barone et al 2020].
• Respiratory failure is a potentially life-threatening complication of tyrosinemia type I, most often occurring as part of an acute neurologic crisis in untreated or poorly managed individuals. These crises are rare in the era of early diagnosis and effective therapy but remain a critical concern, especially if treatment is interrupted or delayed [Dawson et al 2020].
• Hepatocellular carcinoma. Those children who are not treated with nitisinone and a low-tyrosine diet and who survive the acute onset of liver failure are at high risk of developing and succumbing to hepatocellular carcinoma.

Treated tyrosinemia type I. The natural history in children who are treated with nitisinone is different from that of untreated children, especially those individuals diagnosed through NBS and started early on therapy. Affected children younger than age two years who are treated with a combination of nitisinone and low-tyrosine diet have markedly less clinical manifestations compared to those children treated with low-tyrosine diet alone. The combined nitisinone and low-tyrosine diet treatment has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets [McKiernan 2006, Masurel-Paulet et al 2008, Larochelle et al 2012, Kehar et al 2024].

• Neurologic crises observed in treated children have always been associated with a prolonged interruption in nitisinone treatment [Schlump et al 2008].
• Children with acute liver failure require support prior to and during the initiation of treatment with nitisinone. Improvement generally occurs within one week of starting nitisinone treatment.
• Corneal crystals. Nitisinone blocks the tyrosine catabolic pathway such that succinylacetone is not produced but tissue tyrosine levels are raised. Blood tyrosine concentration greater than 600 mol/L confers risk of precipitation of tyrosine as bilateral, linear, branching subepithelial corneal opacities causing photophobia and itchy, sensitive eyes [Ahmad et al 2002]. The crystals resolve once tyrosine levels are reduced.
• Hepatocellular carcinoma. Nitisinone therapy has dramatically reduced – but not eliminated – the risk of hepatocellular carcinoma in individuals with tyrosinemia type I [Holme & Lindstedt 2000, van Spronsen et al 2005, Das 2017, van Ginkel et al 2019]. The risk of hepatocellular carcinoma is closely linked to the age at which nitisinone is started and the degree of liver damage present at diagnosis. When nitisinone is started in infancy, especially in those identified by NBS, the risk of hepatocellular carcinoma is extremely low, estimated at around 5% or less [Larochelle et al 2012].

Genotype-Phenotype Correlations

In general, no correlation is observed between clinical presentation and genotype. Acute and chronic forms have been seen in the same families, as well as in unrelated individuals with the same genotype [Poudrier et al 1998, Morrow et al 2017].

Nomenclature

Tyrosinemia type I has also been referred to as "tyrosinosis," although this is a less specific term.

Prevalence

In geographic areas without NBS, tyrosinemia type I affects approximately one in 90,000 to 120,000 births [Mitchell et al 2001, Angileri et al 2015, Tanguay 2017, Äärelä et al 2020].

In the general US population, the carrier frequency is estimated at one in 100 to one in 150.

Several recurrent variants have been identified in affected individuals from Scandinavian countries including c.1062+5G>A, c.1009G>A, and c.744delG; a birth prevalence of one in 74,800 was reported in Norway [Bliksrud et al 2012]. The most common FAH pathogenic variant in Finland is c.786G>A, where the birth prevalence of tyrosinemia type I is estimated at one in 60,000 [Angileri et al 2015].

A founder effect from colonization by French settlers is present in the province of Quebec, Canada. FAH pathogenic variant c.1062+5G>A accounts for 87% of pathogenic variants in this population. The birth prevalence of tyrosinemia type I in the province of Quebec is one in 16,000. In the Saguenay-Lac Saint-Jean region of Quebec, it is one in 1,846 live births. The overall carrier frequency in Quebec is one in 66 based on NBS data. The carrier frequency in the Saguenay-Lac Saint-Jean region is one in 16 to one in 20 [De Braekeleer & Larochelle 1990, Angileri et al 2015].

Abnormal Newborn Screening (NBS) Result

Elevated tyrosine concentration on NBS can be the result of transient tyrosinemia of the newborn, tyrosinemia type II, tyrosinemia type III [Kahraman et al 2022], or other liver disease.

Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism (e.g., adenosine kinase deficiency [OMIM 614300] and S-adenosylhomocysteine hydrolase deficiency [OMIM 613752)], or classic homocystinuria (see Homocystinuria due to Cystathionine Beta-Synthetase Deficiency).

The detection of succinylacetone in the NBS specimen is pathognomonic for tyrosinemia type I.

Symptomatic Individual

When evaluating a symptomatic individual for tyrosinemia type I, it is essential to consider other genetic disorders (see Table 3) and acquired conditions (e.g., non-genetic causes of liver disease) that can present with similar clinical features, especially in infants and young children with liver dysfunction, renal tubular disease, or poor growth. Clinical correlation is recommended.

Evaluation of a Newborn with an Out-of-Range Newborn Screening (NBS) Result

To confirm the diagnosis and establish the extent of disease and needs in an individual with a positive NBS for tyrosinemia type I, the evaluations summarized in Table 4 are recommended.

Evaluations Following Initial Confirmatory Diagnosis

To establish the extent of disease and needs of an individual with tyrosinemia type I following diagnosis, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

In addition to evaluations by a metabolic specialist and metabolic dietician, frequent evaluation of the parameters summarized in Table 10 are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Agents/Circumstances to Avoid

Avoid the following:

• Excessive dietary protein or protein malnutrition inducing catabolic state
• Prolonged fasting
• Catabolic illness (intercurrent infection, brief febrile illness post vaccination)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

Evaluation of Relatives at Risk

Testing of at-risk sibs of any age is warranted to allow for early diagnosis and prompt initiation of treatment of tyrosinemia type I.

Prenatal testing of a fetus at risk. If the pathogenic variants causing tyrosinemia type I in the family are known, prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to facilitate institution of treatment at birth.

Newborn sib. If prenatal testing was not performed, then – in parallel with NBS – urine and blood succinylacetone should be analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy. FAH molecular genetic testing can be performed if the pathogenic variants in the family are known.

Older sibs. Molecular genetic testing for the familial FAH pathogenic variants or, if the pathogenic variants in the family are not known, analysis for urine succinylacetone in healthy older sibs can be considered.

See Genetic Counseling for issues related to testing at-risk relatives for genetic counseling purposes.

Pregnancy Management

Several case reports describe women with tyrosinemia type I who continued nitisinone therapy throughout pregnancy and delivered healthy children. In these reports, both maternal and neonatal outcomes were generally good, with normal development reported in the children [Garcia Segarra et al 2010, Vanclooster et al 2012, Äärelä et al 2020, Medina et al 2020, Zöggeler et al 2021]. In one instance, an affected woman gave birth to an affected child. The child is reported to have normal growth and development at age seven months [Garcia Segarra et al 2010]. The authors speculate that the affected child was protected from in utero liver damage by maternal treatment with nitisinone during pregnancy.

See MotherToBaby for more information on medication exposure during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Tyrosinemia type I is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an FAH pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FAH pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an FAH pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has tyrosinemia type I or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in FAH.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an FAH pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FAH pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with tyrosinemia type I, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Prevalence and Table 11).
  Note: The American College of Medical Genetics and Genomics includes tyrosinemia type I among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FAH pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for tyrosinemia type I are possible.

Biochemical testing. Prenatal testing for pregnancies at 25% risk is possible by detection of succinylacetone in amniotic fluid obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation. Although detection of succinylacetone in amniotic fluid is diagnostic, false negative results have been reported; thus, this method should only be used by laboratories consistently able to identify succinylacetone at low levels by stable isotope detection. While some reference and academic laboratories may provide succinylacetone quantification in amniotic fluid, it is not universally available and is not considered a routine clinical test in most settings. Because of these issues with biochemical testing, molecular genetic testing is the preferred method of prenatal diagnosis.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Fumarylacetoacetase (FAH) is the terminal enzyme in the tyrosine catabolic pathway (see Figure 1). FAH catalyzes the conversion of fumarylacetoacetate (FAA) to fumarate and acetoacetate and the conversion of succinylacetoacetate to succinate and acetoacetate.

Figure 1.

The tyrosine catabolic pathway FAH = fumarylacetoacetate hydrolase; HPPD = hydroxyphenylpyruvate dioxygenase; PBG = porphobilinogen

In FAH deficiency, FAA appears to accumulate in hepatocytes, causing cellular damage and apoptosis. FAA is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the hepatic enzyme p-hydroxyphenylpyruvic acid dioxygenase (p-HPPD), resulting in elevation of plasma tyrosine concentration and porphobilinogen (PBG) synthase, resulting in (1) reduced activity of the enzyme delta-aminolevulinic acid (δ-ALA) dehydratase in the liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-ALA, which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.

Mechanism of disease causation. Loss of function

FAH-specific laboratory technical considerations. FAH missense variant c.1021C>T (p.Arg341Trp) is described as a pseudodeficiency variant; individuals homozygous for this variant do not develop tyrosinemia type I [Rootwelt et al 1994, Bergeron et al 2001].

Author Notes

Dr Can Ficicioglu (ude.pohc@ulgoicicif) is actively involved in clinical research regarding individuals with tyrosinemia type I. He would be happy to communicate with persons who have any questions regarding diagnosis of tyrosinemia type I or related disorders in tyrosine pathway.

Dr Ficicioglu is also interested in hearing from clinicians treating families affected by isolated hypertyrosinemia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Author History

Can Ficicioglu, MD, PhD (2025-present)
C Ronald Scott, MD; University of Washington (2006-2025)
Lisa Sniderman King, MSc, CGC; Genzyme Corporation (2006-2025)
Cristine Trahms, MS, RD; University of Washington (2006-2025)

Revision History

• 20 November 2025 (sw) Comprehensive update posted live
• 25 May 2017 (ma) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 21 October 2008 (cg) Comprehensive update posted live
• 24 July 2006 (me) Review posted live
• 29 June 2005 (crs) Original submission

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