Hereditary Tyrosinemia type I

Hereditary Tyrosinemia type I (HT1) is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), which functions in the last step of the tyrosine breakdown cascade. Tyrosinemic patients suffer from progressive liver failure during infancy, kidney damage and early development of hepatocellular carcinoma. The substrate of FAH, fumarylacetoacetate (FAA) is thought to be hepatotoxic and mutagenic.
HT-1 patients are currently treated with NTBC, a drug blocking tyrosine catabolism upstream of FAH, thereby preventing accumulation of the toxic metabolite FAA. Unfortunately patients still develop hepatocellular carcinoma (HCC), despite the NTBC treatment.

In our lab we have mice that are FAH-deficient and have a neonatal lethal phenotype that can be rescued by treating the pregnant and nursing female with NTBC. Withdrawing adult FAH-deficient mice from NTBC elicits the HT1 phenotype. Without treatment these mice die within 4-8 weeks. FAH-deficient mice receiving life-long treatment with 1 mg/kg NTBC per day do develop HCC after 8-15 months.

When treating FAH-deficient mice on NTBC with homogentisic acid FAA, a toxic metabolite, can accumulate again. These mice become very ill within 4 hours and will die of acute liver damage. When treating FAH-deficient mice that were withdrawn from NTBC for 15 days, with the same dose of HGA these mice survive this lethal dose of HGA. FAH-deficient mice withdrawn from NTBC seem to have developed a resistancy to cell death caused by HGA.

Failure of cell-death programs, for example as a result of resistance to HGA, may lead to accumulation of damaged cells and enhance the risk for cancer. The goal of this project is to investigate the different pathways leading to cell death in our mouse models.

Theses:

Marjanka Luijerink - Novel insights into the pathogenesis of Hereditary Tyrosinemia Type 1. 16 November 2004
Saskia Jacobs - Hereditary Tyrosinemia type 1 revisited. 1 November 2005