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Congenital erythropoietic porphyria

Karl E Anderson, MD, FACP
Section Editors
Donald H Mahoney, Jr, MD
Moise L Levy, MD
Deputy Editor
Jennifer S Tirnauer, MD


The porphyrias are metabolic disorders caused by altered activities of enzymes within the heme biosynthetic pathway. Congenital erythropoietic porphyria (CEP; OMIM #263700, also called Günther disease) is a rare, autosomal recessive porphyria. It results from an inherited deficiency of the heme biosynthetic enzyme uroporphyrinogen III synthase (UROS; EC, hydroxymethylbilane hydrolase [cyclizing]) [1,2].

In patients with CEP, reduced UROS activity in developing red blood cell precursors causes accumulation of pathogenic heme intermediates (porphyrin isomers uroporphyrin I and coproporphyrin I) during hemoglobin synthesis; porphyrins are also elevated in mature red blood cells, plasma, feces, teeth, and bones. These accumulated porphyrins cause hemolytic anemia and severe cutaneous photosensitivity. In addition, the teeth, bones, and urine of affected individuals contain excess porphyrins and are often red or brown and fluoresce on exposure to light, especially with a wavelength of 400 to 420 nm.

The pathophysiology, diagnosis, and management of CEP will be reviewed here [3]. A general overview of the porphyrias and detailed discussions of the other cutaneous porphyrias are presented separately. (See "Porphyrias: An overview" and "Erythropoietic protoporphyria and X-linked protoporphyria" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Clinical manifestations and diagnosis".)


Enzymatic defect — In the heme biosynthetic pathway, uroporphyrinogen III synthase (UROS, previously termed uroporphyrinogen III cosynthase), catalyzes the conversion of the linear tetrapyrrole hydroxymethylbilane (HMB) to the cyclic tetrapyrrole uroporphyrinogen III (figure 1). This occurs with inversion of one of the four pyrroles, which becomes ring D of the product uroporphyrinogen III (see step 4 in the figure) (figure 1 and figure 2) [4]. Patients with congenital erythropoietic porphyria (CEP) lack normal UROS activity, and as a result the HMB intermediate accumulates excessively in bone marrow red blood cell (RBC) precursors that are actively synthesizing hemoglobin. HMB does not accumulate in the liver or other tissues that synthesize heme.

Excess HMB is converted non-enzymatically (by spontaneous ring closure without inversion of pyrrole ring D) to the non-physiologic porphyrin isomer uroporphyrinogen I (figure 2), some of which is then enzymatically converted to coproporphyrinogen I by uroporphyrinogen decarboxylase, as in step 5 of the figure (figure 1). Coproporphyrinogen I cannot be metabolized further, because coproporphyrinogen oxidase is stereospecific for the coproporphyrinogen III isomer. The excess porphyrinogens that accumulate in CEP are oxidized nonenzymatically to the corresponding porphyrins, primarily uroporphyrin I and coproporphyrin I, which are markedly elevated in circulating erythrocytes, plasma, urine and feces. These porphyrins are also deposited in teeth and bones.

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Literature review current through: Nov 2017. | This topic last updated: Jul 11, 2017.
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