A male patient, born to unrelated Belgian parents, presented at 4 months with
epistaxis, haematemesis and haematochezia. On physical examination he presented
petechiae and haematomas, and a slightly
enlarged liver. Serum
transaminases were elevated to 5-10 times upper limit of normal, alkaline
phosphatases were 1685 U/L (<720), total
bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 microM (<32), prothrombin time less than 10%,
thromboplastin time >180 s (<60) and
alpha-fetoprotein 29723 microg/L (<186). Plasma
tyrosine (651 microM) and
methionine (1032 microM) were strongly increased. In urine,
tyrosine metabolites and
4-oxo-6-hydroxyheptanoic acid were increased, but
succinylacetone and
succinylacetoacetate--pathognomonic for
tyrosinemia type I--were repeatedly undetectable.
Delta-aminolevulinic acid was normal, which is consistent with the absence of
succinylacetone. Abdominal ultrasound and brain CT were normal.Fumarylacetoacetase (FAH)
protein and activity in cultured fibroblasts and liver tissue were decreased but not absent.
4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for
tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH
protein expression.Dietary treatment with
phenylalanine and
tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development.This is the first report of mild
tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites
succinylacetone and
succinylacetoacetate.