Background: Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive inborn error of metabolism caused by deficiency of fumarylacetoacetate hydrolase. HT1 manifests with severe liver and kidney impairment and associates with an increased risk of liver cancer development. The aim of our study is to present a detailed clinical picture and results of biochemical and molecular genetic analyses in 11 Czech patients with HT1 diagnosed in our clinic within 1982-2006.
Methods and results: In 9 patients the disease manifested between 1.5-7 months of age with refusal to eat, failure to thrive and vomiting. In 4 children HT1 progressed to acute liver failure. One clinically healthy boy was diagnosed because of affected sister. In one boy with liver cirrhosis the diagnosis was delayed until the age of 5.5 years. In all children the biochemical investigation showed elevated liver enzymes, alpha1-fetoprotein and hypophosphatemic rickets. Metabolic investigation revealed increased plasma tyrosine level, urinary excretion of succinylacetone and in 8 measured patients also increased urinary delta-aminolevulinic acid concentration. Three patients born before 1988 died due to liver cancer development (two of them) or liver failure. The average age of our 8 living patients is 10.7 +/- 8.3 years. Mutation analysis of FAH gene confirmed the HT1 in these patients and three novel mutations were found in FAH gene: c.579C>A, c.680G>T and c.1210G>A. Clinical status in six patients is favourable on strict low protein diet combined with Orfadin therapy. However, in two children despite of the maximal available therapy lasting 2 and 10 years resp., the disease progressed towards liver cancer development and necessity of liver transplantation.
Conclusions: Early diagnostics of HT1 as a part of extended newborn screening is the only possibility to further improve the prognosis of the patients. Moreover, available molecular-genetic analysis of the FAH gene enables prenatal diagnostics in affected families.