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Key Features

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  • 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

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Clinical Findings

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  • 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

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Diagnosis

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  • 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

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Treatment

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  • 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

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