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At a glance

Elevated blood tyrosine levels are associated with several clinical entities. Depending on the metabolic defect patients have hepatic, renal and neurological manifestations (Type I), oculocutaneous symptoms (Type II), or non-specific problems (Type III).

Synonyms and Classification

  • Tyrosinemia Type I: Hepatorenal Tyrosinemia; Fumarylacetoacetase Deficiency; FAH Deficiency.

  • Tyrosinemia Type II: Oculocutaneous Tyrosinemia; Tyrosine Transaminase Deficiency; Tyrosine Aminotransferase Deficiency; Richner-Hanhart Syndrome; Oregon Type Tyrosinemia.

  • Tyrosinemia Type III: 4-Hydroxyphenylpyruvic Acid Oxydase Deficiency; 4-Hydroxyphenylpyruvate Dioxygenase Deficiency.

Incidence

Tyrosoinemia Type I: The estimated incidence is 1:100,000 live births in the United States, 1:60,000 in Norway, and Quebec (Lac St Jean) 1:16,000 with an incidence of carriers of a specific mutation in 1:14 of the adult population and symptomatic presentation in 1:1850 newborns. Tyrosinemia Type II <1:250,000 and tyrosinemia Type III very rare.

Genetic inheritance

Autosomal recessive in all cases. Mutation of the FAN gene on chromosome 15q23-q25. The sex distribution is equal.

Pathophysiology

Type I: Deficiency of fumarylacetoacetate hydrolase results in a moderate rise in serum tyrosine. Metabolites of tyrosine, including succinylacetone, are thought to be the cause of liver, renal, and neurological damage. Postmortem examination reveals the presence of severe liver and kidney nodular cirrhosis. Type II: Deficiency in tyrosine aminotransferase resulting in high plasma tyrosine concentrations. Type III: Deficiency in 4-hydroxyphenylpyruvate dioxygenase with variable plasma tyrosine concentrations. Transient tyrosinemia (immaturity of the 4-hydroxyphenylpyruvate dioxygenase in the premature who receives no vitamin C supplements) is believed to be the result of delayed enzyme maturation in the tyrosine catabolic pathway. Because it is not caused by a genetic mutation, it does not fall into the category of inborn errors of metabolism.

Diagnosis

Succinylacetone and succinylacetoacetate in blood and urine are diagnostic. Enzyme deficiency demonstrable in liver biopsy specimen or cultured fibroblasts.

Clinical aspects

Transient tyrosinemia of the newborn is benign and disappears spontaneously with no sequelae.

  • Hereditary Infantile Tyrosinemia (Tyrosinemia Type I): Severe form of tyrosinemia. Patients present with peculiar (cabbage-like) odor, renal tubular dysfunction (Fanconi Syndrome), and have a survival rate of fewer than 12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Occasional cases have a later onset; however, the patient is usually younger than age 6 months. This acute form presents with failure to thrive and severe vomiting. Progressive hepatic failure results in death before 2 years of age. Hepatocellular carcinoma may develop. Treatment is now possible with administration of NTBC (2-2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione) inhibits the dioxygenase 4-hydroxyphenylpyruvate and rapidly decreases the production of toxic metabolites. Risk of ocular toxicity with NTBC treatment. Controlled diet required.

  • Richner-Hanhart Syndrome (Tyrosinemia Type II): Distinctly different with herpetiform corneal ulcers and hyperkeratotic lesions of the tongue, digits, palms, and soles, as ...

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