PHARMACOLOGICAL CORRECTION OF NEONATAL LETHAL HEPATIC-DYSFUNCTION IN A MURINE MODEL OF HEREDITARY TYROSINEMIA TYPE-I

Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene d isruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with ro-4-trifluoro-met hylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, correct ed liver function and partially normalized the altered expression patt ern of hepatic mRNAs. The prolonged lifespan of affected animals resul ted in a phenotype analogous to human tyrosinaemia type I including he patocellular carcinoma. The adult FAH(-/-) mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary t yrosinaemia type I as well as hepatic cancer.