A SUGGESTED CONTROL GENE MECHANISM FOR THE EXCESSIVE PRODUCTION OF TYPES I AND III PORPHYRINS IN CONGENITAL ERYTHROPOIETIC PORPHYRIA

The curious phenotype of erythropoietic porphyria, both human and bovine, is directly related to the large amounts of type I porphyrins produced by the developing red cells of the bone marrow. The excessive uroporphyrin (URO-) I is responsible for the photocutaneous manifestations, as well as the red urine, teeth, and bones. The spleen enlarges and is at least partly responsible for the increased destruction of circulating red cells so often observed. This stimulates erythropoiesis and heightened formation of porphyrins, as described elsewhere.l-3 It has been proposed4-7 that the genetic error is a deficiency of uroporphyrinogen (UPG) isomerase. This enzyme directs cyclization to UPG III, of the polypyrryl methane first formed from porphobilinogen (PBG) by PBG deaminase. UPG III is preferentially converted by a decarboxylase to coproporphyrinogen (CPG) III and this by virtue of a coproporphyrinogenase (CPGase), to the corresponding protoporphyrin (PROTO-) and hene. In the absence or relative paucity of isomerase the polypyrryl methane from PBG cyclizes to UPG I, and is decarboxylated in varying proportion to CPG I. With possible rare and minor exceptions,' the specificity of CPGase for type III is maintained, and CPG-I is not converted to a protoporphyrin. Thus, type I porphyrinogens or their respective porphyrins are excreted or accumulated. This has been discussed in recent reviews.4-7 If the inborn error were an isomerase deficiency, a markedly reduced production of type III porphyrin and hemoglobin might be anticipated. It is true that anemia is a frequent accompaniment of the disease and may be severe,2^ 3, 9 but there is no evidence of deficient helme or hemoglobin formation; in fact, this is considerably increased, at times compensating fully for the increased blood destruction.2 Due to the conversion of type III C'PG to PROTO-, thence to heme and bile pigment, the principal evidence of increased type III porphyrin production is found in the excessive fecal urobilinogen excretion, a regular manifestation of the disease when it is sought.4 8, 10 The excess is due in part to increased destruction of circulating red cells, especially in the spleen, but also to a significant, often marked, increase in formation of "early labeled" bile pigment"-"~ unrelated to destruction of the more mature circulating red cells. This fraction may be formed by destruction of young cells, or heime derived from them, even before their entrance into the circulation. A small proportion may be of extraerythropoietic source. The theory that the basic genetic abnormality is a deficiency of isomerase stimulated re-examination of data derived from our earlier studies in the human and bovine disease2 , , 12 and led to some additional observations. Materials and Methods.-The three human cases studied during the past 15 years have been described in detail in earlier papers.2, 3 9 In these, methods were cited for the fecal urobilinogen, urinary and fecal porphyrins, and erythrocyte-free porphyrins. These methods were used in