Tyrosinemia type I is an autosomal recessive inherited metabolic disorder belonging to the group of disorders of amino acid metabolism. The prevalence is approximately 1:100,000. The disorder is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase which results in the last stage of tyrosine metabolism being blocked. The deficiency leads to the accumulation of the metabolites fumarylacetoacetate and maleylacetoacetate, which are converted to succinylacetoacetate and succinylacetone. These substances are toxic to the liver and kidneys and also inhibit the enzyme delta-aminolevulinate dehydratase, a key enzyme in Porphobilinogen synthesis.
The clinical presentation is highly variable. Differentiation between different types is made on the basis of age at onset. The acute type presents in the first weeks and months of life with severe liver disease. The chronic type manifests clinically later with numerous symptoms, in particular liver and kidney dysfunction as well as a vitamin D independent rickets. Both types carry a high risk of developing hepatocellular carcinomas. Moreover, porphyria-like symptoms occur. Nitisinone treatment and a low tyrosine diet alleviate symptoms and progression of the disease.
The defect in enzyme fumarylacetoacetate hydrolase is caused by mutations in the FAH gene. The splice mutations c.554-1G>T (IVS6-1G>T) and c.1062+5G>A (IVS12+5G>A) are frequently the cause in north west European populations and in the Mediterranean region.
A diagnosis is made primarily by laboratory tests. A genetic test is used to confirm a suspected diagnosis.