Erythropoietic protoporphyria

Abstract

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients.

Dual‐wavelength excitation for fluorescence‐based quantification of zinc protoporphyrin IX and protoporphyrin IX in whole blood

“…Overproduction of PPIX, resulting from a gain of function mutation in the rate-limiting erythroid-specific (ALAS2) isoform of mitochondrial 5-aminolevulinate synthase (EC 2.3.1.37), results in marked accumulation of both PPIX and ZnPP in the recently recognized X-linked dominant protoporphyria [11]. Decreased ferrochelatase enzymatic activity in erythropoietic protoporphyria also produces massive increases in erythrocyte PPIX, but without an increase in ZnPP [3,12]. Erythrocyte PPIX may also be elevated in aminolevulinic acid dehydratase deficiency porphyria while ZnPP accumulates in congenital erythropoietic porphyria and hepatoerythropoietic porphyria [13,14].…”

Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria

“…[1][2][3][4] These reactions may be elicited by as little as a few minutes of sun-exposure. 5 Initially, patients suffer from burning pain.…”

Identification and Characterization of an Inhibitory Metal Ion-binding Site in Ferrochelatase

“…Ferrochelatase mutations that lower overall activity below a certain threshold of about 35% result in erythropoietic protoporphyria, a painfully debilitating disease characterized by abnormally high levels of protoporphyrin IX (2). If severe enough, the accumulation of this toxic biochemical intermediate in bodily tissues can lead to extreme photosensitivity and liver failure (3).…”