Rare Diseases Symptoms Automatic Extraction

In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability.

[erythropoietic protoporphyria]

The activity of the erythroid-specific isoenzyme of 5-aminolevulinic acid synthase (ALAS2), the first and rate-limiting enzyme in heme biosynthesis, is down-regulated during iron-deficiency. Ferrochelatase (FECH), the last enzyme of this pathway, inserts iron into protoporphyrin IX (PPIX) to form heme. Patients with erythropoietic protoporphyria (EPP), an inherited deficiency in FECH, often show signs of iron deficiency in addition to phototoxicity which is caused by PPIX accumulation. However, iron supplementation often leads to exacerbation of phototoxicity. We report three EPP patients who had reduced erythrocytic PPIX concentrations when they were iron-deficient and their microcytic and hypochromic anemia deteriorated. Additionally, we found a significant increase in the amount of ALAS2 mRNA and protein among EPP patients. To verify the connection between FECH deficiency and ALAS2 over-expression, we inhibited FECH in cultured cells and found a subsequent increase in ALAS2 mRNA. We conclude that the primary deficiency in ferrochelatase leads to a secondary increase in ALAS2 expression. The combined action of these two enzymes within the heme biosynthetic pathway contributes to the accumulation of PPIX. Furthermore, we hypothesize that EPP patients may benefit from a mild iron deficiency since it would limit PPIX production by restricting ALAS2 over-expression.