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?