Tyrosinemia, Hereditary

Key Features

• Consider in a child who has liver disease with or without accompanying renal disease or bone disease

• Elevated urinary succinylacetone is diagnostic of type 1 tyrosinemia

• Type I tyrosinemia is an autosomal recessive condition caused by deficiency of fumarylacetoacetase

Clinical Findings

• Presents with acute or progressive hepatic parenchymal damage with elevated α-fetoprotein, renal tubular dysfunction with generalized aminoaciduria, hypophosphatemic rickets, or neuronopathic crises

• Tyrosine and methionine are increased in blood and tyrosine metabolites and δ-aminolevulinic acid in urine

• Liver failure may be rapidly fatal in infancy or somewhat more chronic, with a high incidence of liver cell carcinoma in long-term survivors

• Tyrosinemia type II presents with corneal ulcers and keratotic lesions on palms and soles and very high plasma tyrosine levels (> 600 μM)

• Patients with tyrosinemia type III can also have developmental delays and ataxia

Diagnosis

• Increased succinylacetone occurs only in fumarylacetoacetase deficiency and is diagnostic, and is increasingly used in newborn screening

• Diagnosis is confirmed by mutation analysis or by enzyme assay in liver tissue

• Prenatal diagnosis is possible

• Types II and type III are diagnosed by molecular methods

Treatment

• A diet low in phenylalanine and tyrosine ameliorates liver disease, but it does not prevent carcinoma development

• Pharmacologic therapy to inhibit the upstream enzyme 4-hydroxyphenylpyruvate dehydrogenase using 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)

  • Decreases the production of toxic metabolites, maleylacetoacetate and fumarylacetoacetate

  • Improves the liver disease and renal disease

  • Prevents acute neuronopathic attacks

  • Greatly reduces the risk of hepatocellular carcinoma

• Liver transplantation is effective therapy

• Types II and III respond well to dietary tyrosine restriction