Hepatoerythropoietic porphyria: clinical, biochemical, and enzymatic studies in a three-generation family lineage.

Hepatoerythropoietic porphyria is caused by a marked deficiency in the activity of uroporphyrinogen decarboxylase, an enzyme that is essential for heme biosynthesis. It has been hypothesized that uroporphyrinogen decarboxylase deficiency is inherited as a homozygous defect in the disease. This suggestion has been supported by reports of a deficiency of the enzyme in parents of patients with the disorder. Further confirmation would be provided by demonstrating a similar uroporphyrinogen decarboxylase deficiency in the offspring of such patients. This study follows the enzymatic defect throughout three generations of a family in which a second-generation male was shown to have hepatoerythropoietic porphyria. Detailed biochemical and enzymatic analyses revealed a moderate deficiency of uroporphyrinogen decarboxylase in both the proband's parents and in his three children, all of whom were asymptomatic. The mildness of the clinical symptoms in the proband correlated with a higher level of residual enzyme activity than that in previously described patients. We conclude that clinically manifested hepatoerythropoietic porphyria results from the homozygous inheritance of a defect in the uroporphyrinogen decarboxylase gene, that the severity of clinical symptoms is probably related to the level of residual enzyme activity, and that the genetic defect of uroporphyrinogen decarboxylase in hepatoerythropoietic porphyria can be heterogeneous.