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.