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Erythropoietic Protoporphyria, Autosomal Recessive

, MD, MS, , MD, , MD, PhD, FACMG; .

Author Information
, MD, MS
Mount Sinai School of Medicine
New York, New York
, MD
University of Alabama at Birmingham
Birmingham, Alabama
, MD, PhD, FACMG
Mount Sinai School of Medicine
New York, New York

Initial Posting: .

Summary

Disease characteristics. Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness. Vesicular lesions are uncommon. Symptoms, which may seem out of proportion to the visible skin lesions, may persist for hours or days after the initial phototoxic reaction. Photosensitivity usually remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy, similar to that seen in the acute porphyrias. Except for the small minority with advanced liver disease, life expectancy is not reduced.

Diagnosis/testing. Detection of markedly increased free erythrocyte protoporphyrin is the most sensitive and specific biochemical diagnostic test for EPP. Identification of biallelic mutations in FECH, encoding ferrochelatase, confirms the diagnosis.

Management. Treatment of manifestations: There is no FDA-approved treatment for this disease or specific treatment for the acute photosensitivity. The pain is not responsive to narcotic analgesics. The only effective current treatment is prevention of the painful attacks by avoidance of sun/light (including the long-wave ultraviolet light sunlight that passes through window glass) through use of protective clothing (e.g., long sleeves, gloves, wide-brimmed hats, protective tinted glass for cars and windows). Although topical sunscreens are typically not useful, some tanning products containing creams which cause increased pigmentation may be helpful. Oral Lumitene™ (β-carotene) may improve tolerance to sunlight by causing mild skin discoloration due to carotenemia. Severe liver complications are difficult to treat: cholestyramine and other porphyrin absorbents (to interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion) and plasmapheresis and intravenous hemin are sometimes beneficial. Liver transplantation may be required.

Prevention of secondary complications: Vitamin D supplementation to prevent vitamin D insufficiency due to sun avoidance.

Surveillance: Monitoring of: hepatic function every 6-12 months and hepatic imaging if cholelithiasis is suspected; erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile annually; vitamin D 25-OH levels.

Agents/circumstances to avoid: Sunlight and UV light; for those with hepatic dysfunction, drugs that may induce cholestasis (e.g., estrogens); for those with cholestatic liver failure, use of protective filters for artificial lights in the operating room to avoid phototoxic damage

Evaluation of relatives at risk: If both FECH mutations have been identified in an affected family member, at-risk relatives with biallelic mutations can be tested as newborns or infants to allow early intervention (sun protection) and future monitoring for signs of liver dysfunction.

Therapies under investigation: Clinical trials are underway for afamelanotide, α-melanocyte stimulating hormone analogue, which increases skin pigmentation by increasing melanin production.

Genetic counseling. EPP is inherited in an autosomal recessive manner. In 90%-95% of cases an affected individual inherits a loss-of-function FECH allele from one parent and a low-expression FECH allele from the other parent. In about 5%-10% of cases, an affected individual has two loss-of-function FECH alleles. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.

Diagnosis

Erythropoietic protoporphyria (EPP) should be suspected in individuals with the following findings:

  • Cutaneous photosensitivity, usually beginning in childhood
  • Burning, pain, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling
  • Burning, itching, and intense pain; may occur without obvious skin damage
  • Edema of the skin; may be diffuse and resemble angioneurotic edema
  • Absent or sparse vesicles and bullae (Note: The absence of skin damage [e.g., scarring], vesicles, and bullae often make it difficult to establish the diagnosis.)
  • Hepatic dysfunction may occur in 20%-30% of patients and as many as 5% have severe liver disease that may be life threatening, necessitating liver transplantation

Detection of markedly increased free erythrocyte protoporphyrin is the most sensitive and specific biochemical diagnostic test for EPP (Table 1). Identification of biallelic mutations in FECH, encoding ferrochelatase, confirms the diagnosis (Table 2).

Testing

Table 1. Biochemical Characteristics of Erythropoietic Protoporphyria (EPP)

Deficient EnzymeEnzyme ActivityErythrocytesUrineStoolOther
Ferrochelatase 1~10%-30% of normal 2Free protoporphyrin: increased 3, 4, 5, 6Protoporphyrins: not increasedProtoporphyrin: normal or increasedPlasma porphyrins: increased 7, 8

1. Deficient activity of ferrochelatase (EC 4.99.1.1), encoded by FECH, leads to the systemic accumulation of free protoporphyrin and a markedly lesser amount of zinc-chelated protoporphyrin, particularly in erythroid and hepatic cells.

2. The assay for the enzyme ferrochelatase is not widely available and is not used for diagnostic purposes.

3. In EPP, free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin.

4. Many assays for erythrocyte protoporphyrin or “free erythrocyte protoporphyrin” measure both zinc-chelated protoporphyrin and free protoporphyrin. Free protoporphyrin is distinguished from zinc-chelated protoporphyrin by ethanol extraction or HPLC.

5. Protoporphyrins (usually zinc-chelated protoporphyrin) are also increased in lead poisoning, iron deficiency, anemia of chronic disease, and various hemolytic disorders, as well as in those porphyrias caused by biallelic mutations (e.g., harderoporphyria), which are more severe than the acute autosomal dominant porphyrias (e.g., hereditary coproporphyria) caused by heterozygous mutation of the same gene (e.g., CPOX).

6. In X-linked protoporphyria (XLP), resulting from gain-of-function mutations in exon 11 of ALAS2, both free and zinc-chelated protoporphyrins are increased (see Differential Diagnosis).

7. Plasma porphyrins of the III-isomer series are usually increased.

8. Plasma total porphyrins are increased in porphyrias with cutaneous manifestations including EPP. If plasma porphyrins are increased, the fluorescence emission spectrum of plasma porphyrins at neutral pH can be characteristic and can distinguish EPP from other porphyrias. The emission maximum in EPP occurs at 632-634 nm.

Molecular Genetic Testing

Gene. FECH, which encodes the enzyme ferrochelatase, is the only gene in which mutations are known to cause EPP.

Individuals with EPP have mutations in both FECH alleles.

  • About 90% of affected individuals are compound heterozygotes for a mutant allele resulting in markedly decreased ferrochelatase activity and a second low-expression mutant allele (IVS3-48T>C) resulting in residual ferrochelatase activity.

    In populations in which a low-expression allele is quite common (see Prevalence), the disorder may appear to be “pseudodominant,” i.e., an autosomal recessive condition present in individuals in two or more generations of a family, thereby appearing to follow a dominant inheritance pattern. An example is the low-expression allele resulting from the cryptic splicing mutation IVS3-48T>C that has an allele frequency of about 10% in healthy individuals of European descent [Gouya et al 1999, Gouya et al 2002].
  • In about 4% of families with EPP, two loss-of-function FECH mutations are inherited resulting in very low levels of functional ferrochelatase [Whatley et al 2010].

Methods for detecting these large duplications or deletions can be used when biochemical testing is clearly diagnostic and mutations in ALAS2 causing XLP have been ruled out [see Whatley et al 2007].

Table 2. Summary of Molecular Genetic Testing Used in Erythropoietic Protoporphyria

Gene Symbol 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FECHSequence analysis 4Sequence variants 5~91.5%
Deletion/duplication analysis 6Exonic or whole-gene deletions~8.5% 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. In addition to flanking intronic regions, sequence analysis must include deep regions of at least some introns to detect splicing or other mutant alleles (in particular, intron 3 with the IVS3-48T>C variant).

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. See Whatley et al [2007].

Testing Strategy

To confirm/establish the diagnosis of EPP in a proband. For individuals with EPP-like photosensitivity, measurement of erythrocyte protoporphyrin is the most sensitive and specific biochemical diagnostic test for EPP (Table 1). Note: It is important to confirm the diagnosis by an assay that distinguishes free protoporphyrin and zinc-chelated protoporphyrin as several other conditions may lead to elevation of erythrocyte protoporphyrins (see Table 1 footnote 3).

Molecular genetic testing is the definitive test for EPP:

1.

Perform sequence analysis.

2.

If only one or no mutation is identified, perform deletion/duplication analysis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Photosensitivity. Onset of photosensitivity is typically in infancy or childhood (with the first exposure to sun); in most individuals with EPP, the photosensitivity remains for life.

Most individuals with erythropoietic protoporphyria (EPP) develop acute cutaneous photosensitivity within 5-20 minutes upon exposure to sun or ultra-violet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region.

The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Vesicular lesions are uncommon.

Affected individuals are also sensitive to sunlight that passes through window glass that does not block long-wave UVA or visible light.

Cutaneous manifestations. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. The dorsum of the hands is most notably affected.

Severe scarring is rare, as are pigment changes, friability, and hirsutism.

Unlike other cutaneous porphyrias, blistering and scarring rarely occur.

Palmar keratoderma has been observed in some individuals with two loss-of-function FECH alleles [Holme et al 2009, Méndez et al 2009, Minder et al 2010]. Keratoderma was present in 11 of 22 individuals with EPP from 18 families with two severe loss-of-function alleles (in contrast to one severe loss-of-function allele and the low-expression allele) [Minder et al 2010].

Hepatobiliary manifestations. Protoporphyrin is not excreted by the kidneys, but is taken up by the liver and excreted in the bile. Accumulated protoporphyrin in the bile can form stones, reduce bile flow, and damage the liver. Protoporphyric liver disease may cause severe abdominal pain, especially in the right upper quadrant, and back pain.

Gallstones composed in part of protoporphyrin may be symptomatic in individuals with EPP and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation.

About 20-30% of individuals with EPP have some degree of liver dysfunction. In most cases, the hepatic manifestations are mild with slight elevations of the liver enzymes. However, up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure. In most individuals, underlying liver cirrhosis is already present; however, some may present with rapidly progressive cholestatic liver failure.

Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in acute porphyrias. Comorbid conditions, such as viral hepatitis, alcohol abuse, and use of oral contraceptives, which may impair hepatic function or protoporphyrin metabolism, may contribute to hepatic disease in some [McGuire et al 2005].

Hematologic. Anemia and abnormal iron metabolism can occur in EPP. Mild anemia with microcytosis and hypochromia or occasionally reticulocytosis can be seen; however, hemolysis is absent or mild.

Vitamin D deficiency. Persons with EPP who avoid sun/light are at risk for vitamin D deficiency [Holme et al 2008, Spelt et al 2009, Wahlin et al 2011a].

Precipitating factors. Unlike the acute hepatic porphyrias, the only known precipitating factor for EPP is sun/light.

Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [Anderson et al 2001, Wahlin et al 2011a].

Pathophysiology

The deficient activity (10%-35% of normal) of ferrochelatase results in EPP.

Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin that is excreted in bile and feces. At times, the liver may be an important source of excess protoporphyrin, but measuring its contribution relative to that of the erythron has not been possible.

Most of the excess protoporphyrin in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin leakage from these cells is proportional to their protoporphyrin content. Erythrocyte protoporphyrin in EPP is more than 90% free and not complexed with zinc. The content of free protoporphyrin in these cells declines much more rapidly when red cells age than it does in conditions in which erythrocyte zinc-chelated protoporphyrin is increased. Moreover, ultraviolet light may cause free protoporphyrin to be released from the red cell even without disruption of the red cell membrane. In this manner, free protoporphyrin may then diffuse into the plasma (where it is bound to albumin) and be taken up by the endothelium of blood vessels.

The skin of persons with EPP is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called Soret band (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins). When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes.

Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage. Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, acid glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease [Schneider-Yin et al 2000].

As noted, individuals with EPP seem predisposed to develop gallstones that are fluorescent and contain large quantities of protoporphyrin. This and other hepatobiliary complications relate to uptake and excretion of protoporphyrin by the liver [Bloomer 1988]. This dicarboxyl porphyrin is not soluble in aqueous solution and is therefore not excreted in urine.

Long-term observations of patients with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces. On the other hand, severe hepatic complications, when they do occur, often follow increasing accumulation of protoporphyrin in erythrocytes, plasma, and liver. Iron deficiency and factors that impair liver function sometimes contribute. Enterohepatic circulation of protoporphyrin may favor its return and retention in the liver, especially when liver function is impaired. Liver damage probably results at least in part from protoporphyrin accumulation itself, as this porphyrin is insoluble, tends to form crystalline structures in liver cells, can impair mitochondrial functions in liver cells, and can decrease hepatic bile formation and flow [Bloomer 1988, Anderson et al 2001].

Genotype-Phenotype Correlations

The only known genotype/phenotype correlation in EPP is palmar keratoderma reported in persons with two “loss-of-function” FECH mutations [Holme et al 2009, Méndez et al 2009, Minderet al 2010].

Although some reports have indicated that null mutations in FECH may be associated with liver complications [Minder et al 2002], the determinants of liver failure in these individuals are unclear.

Penetrance

EPP appears to be 100% penetrant when there are biallelic FECH mutations or compound heterozygosity for a FECH mutation and a variant that causes low expression of the other FECH allele.

Nomenclature

Obsolete terms for EPP are: erythrohepatic protoporphyria, heme synthetase deficiency, ferrochelatase deficiency

Prevalence

EPP is the third most common porphyria, with an incidence of about 2 to 5 per 1,000,000; it is the most common porphyria in children.

EPP is equally common in women and men. The prevalence ranges from 1:75,000 in the Netherlands (as the result of a founder effect) to 1:200,000 reported in Wales [Holme et al 2006].

EPP has been described worldwide. The prevalence of EPP may vary based on the population allele frequency of the low-expression IVS3-48T>C allele, which ranges from approximately 1% in African Americans to approximately 43% in Japanese.

Differential Diagnosis

Other causes of the erythropoietic protoporphyria (EPP) phenotype include the following:

Acquired causes

  • Polymorphous light eruption
  • Solar urticaria
  • Drug-induced photosensitivity

Acquired late-onset EPP phenotype has been described in rare instances secondary to myelodysplastic syndrome caused by somatic mutation(s) that decrease ferrochelatase activity, presumably a result of the genomic instability associated with the myelodysplasia [Aplin et al 2001, Sarkany et al 2006, Blagojevic et al 2010].

X-linked protoporphyria (XLP) (also known as EPP, X-linked) is caused by gain-of-function mutations in exon 11 of ALAS2 (the gene encoding erythroid-specific 5-aminolevulinate synthase). In males the phenotype is clinically indistinguishable from that of EPP caused by two FECH mutations; in female heterozygotes the phenotype is more variable [Whatley et al 2008]. A higher percentage of persons with liver dysfunction have been reported with XLP; however, this report is based on experience with only eight families.

In XLP, the ratio of free protoporphyrin to zinc-chelated protoporphyrin may range from 90:10 to 50:50 (Table 3). Plasma levels of protoporphyrin are elevated.

Table 3. Biochemical Characteristics of X-Linked Protoporphyria (XLP)

Deficient EnzymeEnzyme ActivityErythrocytesUrineStoolOther
Erythroid-specific 5-aminolevulinate synthase>200% 1 of normalFree protoporphyrin: zinc-chelated protoporphyrin= 90:10 to 50:50Protoporphyrins: Not detectableProtoporphyrin: Normal or increasedPlasma porphyrins: Increased

1. Increased activity due to “gain-of-function” mutations in ALAS2 exon 11

Possible additional genetic loci. It is presumed that mutation at additional loci may cause the EPP phenotype (i.e., cutaneous photosensitivity and elevated erythrocyte protoporphyrins). Molecular epidemiology studies in the UK have identified a FECH or ALAS2 mutation in only 94% of persons with the EPP phenotype [Whatley et al 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with erythropoietic protoporphyria (EPP), the following evaluations are recommended:

  • Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing
  • Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected
  • Medical genetics consultation

Treatment of Manifestations

Acute photosensitivity. There is no FDA-approved treatment for this disease or specific treatment for the acute photosensitivity.

The pain is not responsive to narcotic analgesics.

The only effective current treatment is prevention of the painful attacks by avoidance of sun/light, including the long-wave ultraviolet light sunlight that passes through window glass.

  • Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
  • Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke colored filters provide only partial protection.
  • Tanning products. Some tanning creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent are often effective but are not cosmetically acceptable to all. Topical sunscreens are typically not useful.
  • β-carotene. Oral Lumitene™ (120-180 mg/dL) may improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600-800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. While oral β-carotene has typically been used six to eight weeks before summer to reduce photosensitivity, its effectiveness may be limited [Minder et al 2009].

A systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including β-carotene, N-acetyl cysteine, and vitamin C [Minder et al 2009].

Hepatic disease. Some affected individuals develop severe liver complications which are difficult to treat, often requiring liver transplantation [Anderson et al 2001]. Treatment of hepatic complications, which may be accompanied by motor neuropathy, is difficult.

  • Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [McCullough et al 1988].
  • Plasmapheresis and intravenous hemin are sometimes beneficial [Do et al 2002].
  • Liver transplantation has been performed as a life-saving measure in individuals with severe protoporphyric liver disease [McGuire et al 2005, Wahlin et al 2011b]. However, transplant recipients may experience a recurrence of protoporphyric liver disease in the transplanted liver. Combined bone marrow and liver transplantation is indicated in patients with liver failure to prevent future damage to the allografts [Rand et al 2006].

Other. Iron supplementation may be attempted in persons with anemia and abnormal iron metabolism; close monitoring is warranted. Both clinical improvement and increased photosensitivity have been reported during iron replacement therapy [Holme et al 2007, Lyoumi et al 2007].

Prevention of Secondary Complications

Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency due to sun avoidance.

Immunization for hepatitis A and B is recommended

Surveillance

Annual assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile is appropriate.

Hepatic function should be monitored every six to 12 months. Hepatic imaging studies including abdominal sonogram are indicated if cholelithiasis is suspected.

Vitamin D 25-OH levels should be monitored in all patients whether or not they are receiving supplements.

Agents/Circumstances to Avoid

The following are appropriate:

  • Avoidance of sunlight and UV light
  • In patients with hepatic dysfunction, avoidance of drugs which may induce cholestasis (e.g., estrogens)
  • In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [Wahlin et al 2008]

Evaluation of Relatives at Risk

If both FECH mutations have been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with biallelic mutations can benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is not complicated by EPP. There may be some improvement in photosensitivity during pregnancy as well as a reduction in protoporphyrin levels [Poh-Fitzpatrick 1997].

Therapies Under Investigation

Recent clinical trials with a subcutaneous insertion of a biodegradable, slow-released α-melanocyte-stimulating hormone analog, afamelanotide, which increases pigmentation by increasing melanin, appear promising for the treatment of EPP and XLP (see Differential Diagnosis) [Harms et al 2009, Minder et al 2009, Minder 2010].

  • In Europe Phase 3 trials have been completed and the drug is currently approved for the management of EPP in Italy and pending EMA approval for other countries in the European Union.
  • In the US, Phase 2 trials have been completed and Phase 3 trials are currently underway in order for the drug to receive FDA approval.

Gene therapy has been evaluated only in the murine EPP model to date [Richard et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Erythropoietic protoporphyria (EPP) is inherited in an autosomal recessive manner.

Note: Because of the relatively high carrier frequency of a low-expression FECH allele in some populations, and the observation of two-generation occurrence in some families, EPP was initially thought to be inherited in an autosomal dominant manner. However, molecular genetic studies have determined that the inheritance pattern is autosomal recessive.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele) for either a FECH loss-of-function allele or the common low-expression FECH allele.
    • Most often one parent transmits the loss-of-function FECH allele and the other transmits the common low-expression FECH allele to their affected child.
    • In about 4% of couples, both parents transmit a loss-of-function FECH allele to their affected child.
  • Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic.

Offspring of a proband

  • The offspring of an individual with EPP are obligate heterozygotes (carriers) for a loss-of-function FECH allele or the low-expression FECH allele.
  • Unless an individual with EPP has children with an affected individual or a carrier of a loss-of-function FECH allele or low-expression FECH allele, his/her offspring will be obligate heterozygotes (carriers) for a loss-of-function FECH allele or the low-expression FECH allele. Note: An individual who inherits two copies of the common low-expression FECH allele does not manifest EPP.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as EPP are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Porphyria Foundation (APF)
    4900 Woodway
    Suite 780
    Houston TX 77056-1837
    Phone: 866-273-3635 (toll-free); 713-266-9617
    Fax: 713-840-9552
    Email: porphyrus@aol.com
  • European Porphyria Network
    Email: info1@porphyria-europe.com
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Swedish Porphyria Patients' Association
    CMMS C2-71 Karolinska University Huddinge
    Stockholm Stockholms Lan 141 86
    Sweden
    Phone: +46 8 711 56 09
    Fax: +46 8 585 827 60
    Email: porfyri@swipnet.se
  • RDCRN Patient Contact Registry: Porphyrias Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Erythropoietic Protoporphyria, Autosomal Recessive: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FECH18q21​.31Ferrochelatase, mitochondrialFECH homepage - Mendelian genesFECH

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Erythropoietic Protoporphyria, Autosomal Recessive (View All in OMIM)

177000PROTOPORPHYRIA, ERYTHROPOIETIC; EPP
612386FERROCHELATASE; FECH

Normal allelic variants. Two transcript variants encoding different isoforms have been found for FECH. The transcript variant NM_000140.3 has 11 exons.

Pathologic allelic variants. As of July 2012, more than 165 loss-of-function mutations [Stenson et al 2003; www.hgmd.org] have been identified in FECH, many of which result in an unstable or absent enzyme. Deleterious loss-of-function mutations include missense and nonsense mutations, small deletions, and insertions. The common low-expression allele IVS3-48T>C creates a cryptic splice acceptor site and decreases the frequency of wild-type transcripts to about 25% of normal levels. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism.

Table 4. Selected FECH Pathologic Allelic Variants

DNA Nucleotide Change
(Conventional Nomenclature 1)
Protein Amino Acid ChangeReference Sequences
IVS3-48T>C 2
(c.315-48T>C)
Aberrant splicing of exon 4NM_000140​.3
NP_000131​.2

See Quick Reference for an explanation of nomenclature.

1. Conventional mutation nomenclature: Human Genome Variation Society (www​.hgvs.org)

2. Variant designation that does not conform to current naming conventions

Normal gene product. The normal gene encodes an enzyme of 423 amino acids (NP_000131.2), including a 54-residue polypeptide for localization in the mitochondrion.

Abnormal gene product. FECH mutations result in either a nonfunctional or a partially functional enzyme. The low-expression IVS3-48T>C allele encodes fewer copies of the normal FECH enzyme as a result of defective RNA splicing.

References

Literature Cited

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  14. McCullough AJ, Barron D, Mullen KD, Petrelli M, Park MC, Mukhtar H, Bickers DR. Fecal protoporphyrin excretion in erythropoietic protoporphyria: effect of cholestyramine and bile acid feeding. Gastroenterology. 1988;94:177–81. [PubMed: 3335288]
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  26. Spelt JMC, de Rooij FWM, Wilson JHP, Zandbergen AAM. Vitamin D deficiency in patients with erythropoietic protoporphyria. J Inherit Metab Dis. Available online. 2009. Accessed 7-22-13.
  27. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abevsinghe S Krawczak M, Cooper DN. Human Gene Mutation Database (HGMD). Available online. 2003. Accessed 7-22-13.
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  30. Wahlin S, Stal P, Adam R, Karam V, Porte R, Seehofer D, Gunson BK, Hillingsø J, Klempnauer JL, Schmidt J, Alexander G, O'Grady J, Clavien PA, Salizzoni M, Paul A, Rolles K, Ericzon BG, Harper P. European Liver and Intestine Transplant Association; Liver transplantation for erythropoietic protoporphyria in Europe. Liver Transpl. 2011b;17:1021–6. [PubMed: 21604355]
  31. Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli-Vergani G, Deybach JC, Puy H. 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;83:408–14. [PMC free article: PMC2556430] [PubMed: 18760763]
  32. Whatley SD, Mason NG, Holme SA, Anstey AV, Elder GH, Badminton MN. Gene dosage analysis identifies large deletions of the FECH gene in 10% of families with erythropoietic protoporphyria. J Invest Dermatol. 2007;127:2790–4. [PubMed: 17597821]
  33. Whatley SD, Mason NG, Holme SA, Anstey AV, Elder GH, Badminton MN. Molecular epidemiology of erythropoietic protoporphyria in the united kingdom. Br J Dermatol. 2010;162:642–6. [PubMed: 20105171]

Suggested Reading

  1. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375:924–37. [PubMed: 20226990]
  2. Layer G, Reichelt J, Jahn D, Heinz DW. Structure and function of enzymes in heme biosynthesis. Protein Sci. 2010;19:1137–61. [PMC free article: PMC2895239] [PubMed: 20506125]

Chapter Notes

Acknowledgments

The EPP contribution to GeneReviews was supported in part by the Porphyrias Consortium of the NIH-supported Rare Diseases Clinical Research Network (rarediseasesnetwork.epi.usf.edu; NIH grant: 5 U54 DK083909), including:

  • Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX
  • Dr Montgomery Bissell, University of California, San Francisco, CA
  • Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, NC
  • Dr. John Phillips, University of Utah School of Medicine, Salt Lake City, UT

Revision History

  • 27 September 2012 (me) Review posted live
  • 10 April 2012 (rd) Original submission
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