Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.