Diagnosis and management of tyrosinemia type I.

Hereditary tyrosinemia type I (HTI) (MIM 276700) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (EC 3.7.1.2), which is the last enzyme in the tyrosine degradation pathway. The enzyme block causes accumulation of toxic metabolites in the liver and kidneys, which are the organs where tyrosine is mainly degraded. The disorder is characterized by severe liver disease, which either causes liver failure in infancy or may take a more protracted course, with death often occurring during childhood or adolescence because of hepatoma development. Treatment with a diet restricted in phenylalanine nd tyrosine does not prevent progression of the liver disease and development of hepatocellular carcinoma. Liver transplantation was previously the only option for these patients. Important achievements from metabolic and molecular biology studies of the disease include a new treatment for patients with HTI using an enzyme inhibitor, detection of self-induced correction of the genetic defect in regenerative liver nodules in HTI patients, identification and development of useful animal models for HTI, and studies of the molecular genetics of HTI. These advances will have great implications for our understanding of pathogenetic mechanisms, which is the basis for improved diagnostic methods and improved treatment of patients with HTI.