Erythropoietic porphyria

Presentation

X-linked dominant erythropoietic protoporphyria is a relatively mild form of porphyria. Its predominant symptom is extreme photosensitivity, causing severe itching and burning of the skin due to buildup of protoporphyrin IX. Treatment with supplemental iron for a gastric ulcer reduced free protoporphyrin levels, but zinc-protoporphyrin levels did not decrease.

Cause

X-linked dominant erythropoietic protoporphyria (XDEPP) is caused by a gain-of-function mutation in the ALAS2 gene, which encodes the first enzyme in heme biosynthesis. The mutation results from a frameshift due to one of two deletions in ALAS2 exon 11: c.1706-1709 delAGTG or c.1699-1700 delAT. These alter the 19th and 20th residues of the C-terminal domain, changing the enzyme's secondary structure. The delAGTG deletion, found in several genetically distinct families, replaces an α-helix with a β-sheet.

Previously, ALAS2 mutations caused loss-of-function X-linked sideroblastic anemia. Erythropoietic protoporphyria (EPP) has similar symptoms but results from loss-of-function in FECH, the last enzyme in the pathway. XDEPP is distinct from EPP in that there is no iron overload and no anemia. It is characterized by buildup of protoporphyrin IX due to increased ALAS2 function.

Because FECH is functional, all available Fe2+ is used for heme production, and FECH instead uses Zn2+, leading to accumulation of zinc-protoporphyrin IX.