Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

Abstract

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.

Microcytosis in Erythropoietic Protoporphyria

“…EPP occurs because of a loss-of-function mutation in one allele of the FECH gene, which is primarily inherited in trans to a low expression FECH allele carrying common genetic variants (c.1 –252G, c.68–23T, c.315–48C), causing a 70% reduction in enzymatic activity ( Gouya et al, 2002 ; Chiara et al, 2020 ). FECH deficiency leads to significantly elevated protoporphyrin IX (PPIX) levels mainly in erythrocytes and subsequently in the skin and liver ( Balwani et al, 2017 ; Di Pierro et al, 2022 ). The PPIX accumulation causes lifelong acute photosensitivity with childhood-onset and several degrees of hepatobiliary involvement with acute liver failure occurring in 1–5% of patients ( Anstey and Hift, 2007 ; Wensink et al, 2021 ).…”

Accumulation of Toxic Elements Disrupts Metabolic Processes in the Human: Review

“…Hemes include important proteins, such as hemoglobin and myoglobin [67]. Other complexes can also be formed with zinc (zinc-protoporphyrin ) [68]. Measuring the level of complexes zink protoporphyrin and the level of Lead (Pb) in the blood is evidence of the person's lead poisoning.…”

Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria

“…Both EPP and XLP are erythroid forms of disorders that are categorized as “cutaneous” porphyrias since clinical manifestations are generally limited to photosensitivity ( Phillips, 2019 ). The main distinction is that in EPP one finds accumulation of free protoporphyrin IX while in XLP there is significant accumulation of zinc-protoporphyrin IX ( Di Pierro et al, 2022 ).…”