American Society of Hematology

Erythropoietic Protoporphyria: Multiple Pathways to a Common Phenotype

James P. Kushner, MD
John D. Phillips, PhD

Published on: September 01, 2013

Dr. Kushner and Dr. Phillips indicated no relevant conflicts of interest.

1. Maxwell M. Wintrobe Distinguished Professor of Medicine, Emeritus, Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine

2. Associate Professor, Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine

Abnormalities affecting the function of the FECH (ferrochelatase) complex and delivery of FECH’s substrates are responsible for a group of disorders known as erythropoietic protoporphyria (EPP). Although the heme biosynthetic pathway is active in all cells, the excess protoporphyrin of EPP is derived from erythroid precursors. This situation differs from that observed in the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) where excess porphyrin and porphyrin precursors originate in the liver.

The heme biosynthetic pathway involves eight enzymatic reactions partitioned between the mitochondria and the cytosol (Figure).1 FECH, a homodimer associated with the matrix side of the inner mitochondrial membrane, catalyzes the final step in the pathway, the insertion of iron into protoporphyrin (Figure).2 Each monomer of FECH contains a 2Fe-2S iron-sulfur cluster, which is required for enzymatic activity (Figure).2 The human FECH gene maps to chromosome 18q21.3. FECH is synthesized in the cytosol and targeted to mitochondria by sequences in the leader peptide.3 Recent evidence suggests that FECH functions as part of a multi-enzyme complex associated with the inner mitochondrial membrane (Figure).4 Two members of the complex are required to deliver substrates to FECH, protoporphyrinogen oxidase (PPO) to deliver protoporphyrin and mitoferrin 1 (Mfrn1) to deliver iron (Figure).5 A third member, ABCb10, stabilizes Mfrn1 and likely has additional undefined functions (Figure).4

EPP was characterized and named by Magnus et al. in 1961.6 Those investigators described a 35-year-old man who manifested an unusual reaction to sun exposure that had begun in childhood and was characterized by intense discomfort, redness, and swelling of exposed skin that developed within five minutes of sun exposure. The reaction was termed solar urticaria. High levels of protoporphyrin were found in feces, plasma, and red cells; and marrow erythroid precursors fluoresced. Notably, the patient had a history of cholecystectomy for treatment of a symptomatic gallstone.

The clinical description of EPP has been verified and expanded by many investigators over the past 50 years.1 The photosensitivity is quite different from that seen in other types of cutaneous porphyria (e.g., congenital erythropoietic porphyria and porphyria cutanea tarda) in that bullous lesions, scarring, and pigment changes do not occur. Instead, the skin of sun-exposed areas (primarily facial skin) develops a leathery appearance that mimics premature aging. A mild, microcytic anemia is common, but it is not a uniform finding. Ringed sideroblasts are occasionally noted. Gallstones occur in about 10 percent of EPP patients and usually develop early in life. The liver takes up protoporphyrin from plasma and transfers it to bile where solubility of bile components is altered. There is a vigorous enterohepatic recirculation of biliary protoporphyrin, which further magnifies plasma porphyrin values and adds to the amount of protoporphyrin taken up by the liver. Cholestasis, severe enough to cause progressive and lethal liver disease, occurs in about 5 percent of cases.7

Autosomal Recessive EPP

The discovery of loss-of-function (LOF) FECH mutations coupled with family studies initially suggested that EPP was transmitted as an autosomal dominant trait with variable penetrance, but clinically affected heterozygotes consistently showed FECH activity of only 15 to 20 percent of normal. A dominant negative effect was proposed, but the discovery of a hypomorphic FECH allele established that most cases of EPP represent an autosomal recessive disorder.8 An intragenic polymorphism (IVS3-48C) in intron 3 of the FECH gene favors the use of a cryptic acceptor splice site yielding an aberrantly spliced mRNA that is rapidly degraded. The result is a lower steady-state level of wild-type FECH mRNA. More than 90 percent of clinically evident cases of EPP are due to coinheritance of the hypomorphic (hypo) FECH allele in trans to a LOF mutant allele (genotype FECH hypo/FECH LOF).8 The frequency of the hypomorph allele varies widely in different populations and relates to the observed differences in the prevalence of EPP. EPP is pan-ethnic, but it is extremely rare in individuals of African decent.

A rare exception to the FECH hypo/FECH LOF genotype is inheritance of two FECH LOF alleles (genotype FECH LOF/FECH LOF).8 This form of EPP carries a higher risk of severe cholestatic liver disease.

X-Linked EPP

The application of FECH gene sequencing and the concentration of porphyria patients in centers in the United States, Europe, and South Africa have revealed that 5 to 10 percent of patients with EPP have no FECH mutations.8,9 Whatley et al. studied eight families in the United Kingdom with “mutation-negative” EPP. They displayed a dominant pattern of inheritance with an absence of father-to-son transmission, a finding suggestive of X-chromosome linkage.9 The EPP phenotype was also observed in females due to skewing of X-chromosome inactivation. Erythrocyte protoporphyrin concentrations were higher than in EPP patients with FECH mutations, and the percentage of the zinc chelate (i.e., zinc protoporphyrin) was markedly higher (median 44% vs. 8% in the FECH mutant group). The cause of the EPP phenotype in these families proved to be mutations affecting the carboxy-terminus of the erythroid-specific form of δ-aminolevulinic acid synthase (ALA-S2). The mutations resulted in an increase in specific activity compared with wild-type ALA-S2. The increased production of ALA leads to an increase in flux through the pathway and generates protoporphyrin in excess of the capacity of FECH to produce heme. The large amounts of zinc-protoporphyrin suggested that the metal chelating properties of FECH have not been exceeded and that delivery of iron to the active site of FECH limits heme synthesis.

Others have confirmed the findings of Whatley et al., and a total of five ALA-S2 gain-of-function mutations have been identified, all involving the carboxy-terminus.8-10 The carboxy-terminus of ALA-S2 forms a “flexible” loop over the active site of the enzyme. The “open” position favors release of ALA and likely increases access of substrates to the active site.11 Both effects result in increased enzymatic activity. The carboxy-terminus also enhances the stability and activity of ALA-S2. A carboxy-terminal mutation that ablates the succinyl-CoA synthase binding site causes LOF changes in ALA-S2 and X-linked sideroblastic anemia.12 Surprisingly, one gain-of-function mutation (Q548X) does not bind succinyl-CoA synthase.10 Collectively, the data suggest that conformational changes associated with the carboxy-terminus are the main mechanism determining the specific
activity of ALA-S2.

Acquired EPP

Over a dozen late-onset cases of EPP associated with myelodysplastic and myeloproliferative disorders have been reported, many of which displayed partial or complete loss of chromosome 18 in the affected hematopoietic clone.1 A lateonset case of X-linked EPP has also been reported.13 The acquired gain-of-function mutations in the abnormal hematopoietic clone (Q548X) had previously been detected in an inherited case of X-linked EPP.

Other Causes of EPP

A handful of individuals with the EPP phenotype do not have detectable mutations in FECH or ALA-S2. Abnormal Mfrn1 expression and low-FECH activity were detected in one such case,14 but potential defects in iron-sulfur cluster assemble and transport, iron chaperones, transcription factors, translational regulators, and factors required for assembly of multi-enzyme complexes remain unexplored.


The therapy of EPP is focused on minimizing the harmful effects of exposure to sunlight and on managing the hepatotoxic effects of protoporphyrin. As with other photosensitizing porphyrias, protective clothing and opaque sunscreens are helpful. Tolerance to sunlight can be further enhanced by inducing carotenemia with β-carotene beadlets or darkening skin color with an α-melanocyte stimulating hormone.8 In EPP patients who develop liver failure, liver transplantation is the only effective therapy.7 There is a high risk of recurrent disease in the transplanted liver because of the continued overproduction of protoporphyrin in the native marrow. A bone marrow allograft can avoid this complication and is being employed more often in patients who have undergone a liver transplant.

1. Dailey HA, Meissner PN. Erythroid heme biosynthesis and its disorders. Cold Spring Harb Perspect Med. 2013;3:a011676.

2. Hunter GA, Al-Karadaghi S, Ferreira GC. Ferrochelatase: The convergence of the porphyrin biosynthesis and iron transport pathways. J Porphyr Phthalocyanines. 2011;15:350-356.

3. Whitcombe DM, Carter NP, Albertson DG, et al. Assignment of the human ferrochelatase gene (FECH) and a locus for protoporphyria to chromosome 18q22. Genomics. 1991;11:1152-1154.

4. Chen W, Dailey HA, Paw BH. Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood. 2010;116:628-630.

5. Rhee HW, Zou P, Udeshi ND, et al. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science. 2013;339:1328-1331.

6. Magnus IA, Jarrett A, Prankerd TA, et al. Erythropoietic protoporphyria. A new porphyria syndrome with solar urticaria due to protoporphyrinaemia. Lancet. 1961;2:448-451.

7. Wahlin S, Stal P, Adam R, et al. Liver transplantation for erythropoietic protoporphyria in Europe. Liver Transpl. 2011;17:1021-1026.

8. Balwani M, Doheny D, Bishop DF, et al. Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of x-linked protoporphyria. Mol Med. 2013;19:26-35.

9. Whatley SD, Ducamp S, Gouya L, et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet. 2008;83:408-414.

10. Ducamp S, Schneider-Yin X, de Rooij F, et al. Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP). Hum Mol Genet. 2013;22:1280-1288.

11. Hunter GA, Ferreira GC. Molecular enzymology of 5-aminolevulinate synthase, the gatekeeper of heme biosynthesis. Biochim Biophys Acta. 2011;1814:1467-1473.

12. Bishop DF, Tchaikovskii V, Hoffbrand AV, et al. X-linked sideroblastic anemia due to carboxylterminal ALAS2 mutations that cause loss of binding to the β-subunit of succinyl-CoA synthetase (SUCLA2). J Biol Chem. 2012;287:28943-28955.

13. L ivideanu CB, Ducamp S, Lamant L, et al. Late-onset X-linked dominant protoporphyria: an etiology of photosensitivity in the elderly. J Invest Dermatol. 2013;133:1688-1690.

14. Wang Y, Langer NB, Shaw GC, et al. Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria. Exp Hematol. 2011;39:784-794.

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