Two novel FAH gene mutations in a patient with hereditary tyrosinemia type I

Hereditary tyrosinemia type I (HT I) is a severe inborn metabolic disorder affecting the tyrosine degradation pathway. Most untreated patients die within the first two years of life. HT I results from fumarylacetoacetate hydrolase (FAH) deficiency caused by mutations in the FAH gene. The diagnosis of HT I is confirmed by measuring FAH enzyme activity in cultured fibroblasts or liver tissue and/or detecting disease-causing mutations in the FAH gene.

A female neonate was referred to our hospital for further evaluation of an abnormal newborn screening test that showed elevated tyrosine levels. We analyzed amino acids and organic acids in the patient's blood and urine. To identify the genetic abnormality, all the coding exons and flanking introns of the FAH gene were analyzed via PCR.

A repeat newborn screening test and plasma amino acid analysis revealed increased tyrosine levels in the patient. Urine organic acid analysis showed increased urinary excretion of 4-hydroxyphenyllactate, 4-hydroxyphenylpyruvate, and succinylacetone. Sequence analysis of the FAH gene identified two novel variations (c.536A>G (p.Gln179Arg) and c.913+5G>A) that had not been previously reported and that were not found in 170 healthy controls.

HT I was confirmed in this patient by molecular genetic analysis of the FAH gene, with highly suggestive biochemical findings. The novel sequence variations detected in the present study should be considered disease-causing mutations by in silico analysis. In the Korean population, this is the first described case of HT I caused by a point mutation in the FAH gene.