Also known as: Genetic tyrosinemias


– Tyrosinemia type 1 – gene FAH

  • Also known as: Hepatorenal Tyrosinemia I; Hereditary Tyrosinemia type 1; Fumarylacetoacetase Deficiency; FAH Deficiency
  • OMIM#276700

Tyrosinemia type 2 – gene TAT

  • Also known as: Richner-Hanhart Syndrome; Tyrosine Aminotransferase Deficiency
    TAT Deficiency; Tyrosine Transaminase Deficiency; Keratosis Palmoplantaris With Corneal Dystrophy; Oregon Type Tyrosinemia; Tyrosinosis, Oculocutaneous Type
  • OMIM#276600

Tyrosinemia type 3 – gene HPD

  • Also known as: 4-Hydroxyphenylpyruvic Acid Oxidase Deficiency; 4-Hydroxyphenylpyruvate Dioxygenase Deficiency
  • OMIM#276710

1. The Disease

The genetic tyrosinemias are characterized by the accumulation of tyrosine in body fluids and tissues. The most severe form of tyrosinemia, Type I, is a devastating disorder of childhood that causes liver failure, painful neurologic crises, rickets, and hepatocarcinoma. See about Tyrosinemia 2 and 3 after all the information about HT1.

Tyrosinemia type 1 (HTI) is an inborn error of tyrosine catabolism caused by defective activity of fumarylacetoacetate hydrolase (FAH) and is characterized by progressive liver disease, renal tubular dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with nitisinone. If untreated, death typically occurs at less than 2 years of age, with some chronic forms allowing longer survival. It has a prevalence of about 1 in 100,000 newborns in the general population.

2. The Symptoms

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. HT1 is clinically heterogenous. Symptoms may start during the first few months (acute type), in second half of the first year (subacute type) or in the following years up to adulthood (chronic type).

Infants are usually initially asymptomatic at birth. Lack of early signs or symptoms does not exclude the diagnosis.

  • In the acute type, manifestations of hepatic failure predominate (bleeding diathesis, hypoglycemia, ascites etc) with frequent sepsis and rapid deterioration. Mild proximal tubular disease is usually present.
  • Subacute type manifests a similar but less severe clinical picture presenting usually with hepatomegaly or hypophosphatemic rickets (due to tubular dysfunction). Intercurrent illness may precipitate hepatic crisis.
  • Chronic type presents with hepatomegaly secondary to cirrhosis and often tubulopathy, leading to rickets and renal failure. Neurological crises are infrequent presenting symptoms; however they can complicate any type of the disease when untreated. The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation.
  • All patients stand a high risk of developing hepatocellular carcinoma (HCC) secondary to cirrhosis.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (having 2 mutations or 2 copies of a single mutations in the FAH gene) should continue breastfeeding. Early treatment is essential in preventing chronic symptoms.
  • Biochemical correlation is essential for diagnosis confirmation through NBS with tandem mass spectrometry (MS/MS) for the detection of elevated tyrosine (Tyr) and succinyl-acetone (SA) in dried blood spots.
  • Other abnormalities include elevated α-fetoprotein (especially in acutely ill infants), increased plasma levels of tyrosine, phenylalanine and methionine, increased urinary delta-aminolevulinate (δ-ALA) and features of Fanconi tubulopathy.
  • Hepatorenal Tyrosinemia I is a lifelong disease that requires lifetime compliance to dietary management and regular follow-up with a metabolic disease specialist and a multidisciplinary approach to care.
  • Nitisinone treatment should begin as soon as the diagnosis of tyrosinemia type I is confirmed. Because nitisinone increases the blood concentration of tyrosine, dietary management with controlled intake of phenylalanine and tyrosine should be started immediately after diagnosis to prevent tyrosine crystals from forming in the cornea. If the blood concentration of phenylalanine becomes too low (<20 μmol/L), additional natural protein should be added to the diet.
  • Prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now should be reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

Oculocutaneous tyrosinemia, Type II, is caused by a deficiency of tyrosine aminotransferase (TAT). It clinically presents with hyperkeratotic plaques on the hands and soles of the feet and photophobia due to deposition of tyrosine crystals within the cornea.

Tyrosinemia Type III is an extremely rare disorder caused by a deficiency of 4-hydroxyphenylpyruvic dioxygenase. It has been associated with ataxia and mild mental retardation.

Biochemical correlation is essential for diagnosis confirmation by observing elevated tyrosine by plasma amino acid chromatography and characteristic tyrosine metabolites by urine organic acid analysis.

Therapy consists of a diet low in phenylalanine and tyrosine for each of the tyrosinemias and 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone/ NTBC) only for tyrosinemia Type I.

4. For more information


  • Nakamura K, Matsumoto S, Mitsubuchi H, Endo F. Diagnosis and treatment of hereditary tyrosinemia in Japan. Pediatr Int. 2015; 57(1):37-40. PMID: 25443793.
  • Scott CR. The genetic tyrosinemias. Am J Med Genet C Semin Med Genet. 2006;142C(2):121-126. PMID: 16602095.