Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus.

BACKGROUND Hepatoerythropoietic porphyria (HEP) is usually a severe form of cutaneous porphyria, characterized biochemically by an increased urinary excretion of polycarboxylated porphyrins. The disease is the result of a profound deficiency (<10% of normal activity) of uroporphyrinogen decarboxylase (UROD) activity. Hepatoerythropoietic porphyria is inherited as an autosomal recessive trait, whereas familial porphyria cutanea tarda is dominant. At least 30 different mutations of the UROD gene have been identified in patients with HEP and familial porphyria cutanea tarda, with 1 predominant missense mutation (glycine-to-glutamic acid substitution at codon 281) in Spanish patients with HEP. OBSERVATION A 5-year-old patient with first-degree-related parents presented with HEP and mild symptomatology. We found low levels of UROD enzymatic activity and a new homozygous mutation of the UROD gene, a phenylanine-to-leucine substitution at codon 46 (F46L). Both parents were healthy carriers of the mutation. The mother had reduced UROD activity (50% of normal), whereas the father had normal UROD activity. Prokaryotic expression of the F46L mutation using a pGEX vector has been used to confirm the deleterious effect of the mutation. When the mother started a new pregnancy, a prenatal study showed the absence of F46L mutation in the fetus and no accumulation of porphyrins in the amniotic fluid. CONCLUSIONS A new mutation in the UROD gene causes a mild HEP phenotype. A normal UROD enzymatic activity was observed in the father, despite the presence of the heterozygous mutation. To our knowledge, this observation is the first description of a prenatal exclusion of HEP.