Tyrosinaemia type 1

Hereditary tyrosinaemia type I (HT1) is of autosomal recessive inheritance and is caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The enzyme block leads to accumulation of the fumarylacetoacetate and possibly maleylacetoacetate, which are alkylating agents and are supposed to cause the organ damage of the disorder. HT1 is characterised by progressive liver disease with pronounced regeneration and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. The clinical symptoms are highly variable with onset from infancy to adolescence. In the most acute form the patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinaemia. Untreated these patients die from cirrhosis or hepatocellular carcinoma at a young age.

The frequent development of hepatocellular carcinoma indicates that DNA is unstable in HT1-hepatocytes. The reason behind the labile DNA in hepatocytes of HT1-patients is not fully understood. The aim of the tyrosinaemia project is a better understanding of the relationship between accumulated metabolites and unstable DNA in hepatocytes from patients with HT1.