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.
Highlights
Erythropoietic protoporphyria, Protoporphyria, Haem synthetase deficiency, Ferrochelatase deficiency, X-linked dominant protoporphyria (XLDPP), Erythrohepatic protoporphyria
Erythropoietic protoporphyria (EPP) is a painful photodermatosis without blisters caused by inborn errors of the haem biosynthetic pathway due, in the majority of patients, to a deficient activity of the enzyme ferrochelatase (ferrohaemprotolyase, haem synthetase, ferrohaem-protolyase, EC4.99.1.1, FECH (EPP), (MIM 177000) or caused, in about 2% of patients, by a gain of activity of the erythroid specific aminolevulinic acid synthase 2 (ALAS; EC 2.3.1.27)
ALAS is the first enzyme of the haem synthetic pathway, which is synthesised by two different genes: ALAS1 in the liver and other tissues located on chromosome 3, and ALAS2 in the erythroid tissue located on chromosome X
Summary
Rüfenacht UB, Gouya L, Schneider-Yin X, Puy H, Schäfer BW, Aquaron R, Nordmann Y, Minder EI, Deybach JC: Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria. Gouya L, Martin-Schmitt C, Robreau AM, Austerlitz F, Da Silva V, Brun P, Simonin S, Lyoumi S, Grandchamp B, Beaumont C, Puy H, Deybach JC: Contribution of a single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Herrero C, To-Figueras J, Badenas C, Méndez M, Serrano P, EnríquezSalamanca R, Lecha M: Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease. Chen F-P, Risheg H, Liu Y, Bloomer J: Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease. Minder EI, Gouya L, Schneider-Yin X, Deybach J-C: A genotypephenotype correlation between null allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria.
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