Enzyme defects in the porphyrias and their relevance to the biochemical abnormalities in these disorders.

Defects in enzymes of the heme biosynthesis pathway underlie the biochemical abnormalities which occur in the porphyrias. Porphyrins and porphyrin precursors are accumulated and excreted in excessive amounts because of the enzyme defects. This is illustrated by studies in protoporphyria and variegate porphyria, disorders in which the biochemical abnormalities indicate a defect(s) in the terminal part of the heme biosynthesis pathway. The activity of heme synthease (ferrochelatase), which catalyzes the chelation of ferrous iron to protoporphyrin, is deficient in tissues of patients with protoporphyria. This causes protoporphyrin to be accumulated and excreted excessively. In variegate porphyria protoporphyrinogen oxidase, which catalyzes the oxidation of protoporphyrinogen to protoporphyrin, appears to be defective. As a result, protoporphyrinogen may be excreted in increased amounts in bile, where it is subsequently auto-oxidized to protoporphyrin. The following questions have arisen as a result of the demonstrations of enzyme defects in tissues of patients with porphyria: (1) Will different defects in the same enzyme be found among patients who fulfill the clinical and biochemical criteria for diagnosis of a specific porphyria? That is, does genetic heterogeneity exist in each of the porphyrias? (2) Why do some patients with an enzyme defect not have biochemical abnormalities? (3) Why is one type of tissue, usually the liver, the major site of expression of the biochemical abnormality, when the enzyme defect can be demonstrated in all tissues?