Erythropoietic protoporphyria is an inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase, the terminal enzyme of the heme biosynthetic pathway, which catalyzes the insertion of iron into protoporphyrin to form heme. EPP is ... Erythropoietic protoporphyria is an inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase, the terminal enzyme of the heme biosynthetic pathway, which catalyzes the insertion of iron into protoporphyrin to form heme. EPP is characterized clinically by photosensitivity to visible light commencing in childhood, and biochemically by elevated red cell protoporphyrin levels (Todd, 1994).
Light-sensitive dermatitis commencing in childhood, usually before 10 years of age, is the presenting finding in erythropoietic protoporphyria (Peterka et al., 1965; de Leo et al., 1976). Patients experience itching and burning, and develop erythema even after brief ... Light-sensitive dermatitis commencing in childhood, usually before 10 years of age, is the presenting finding in erythropoietic protoporphyria (Peterka et al., 1965; de Leo et al., 1976). Patients experience itching and burning, and develop erythema even after brief exposure to bright light. Chronic skin changes sometimes occur (Poh-Fitzpatrick, 1978). Herbert et al. (1991) described a second-degree burn of the light-exposed abdominal wall resulting from exposure during liver transplantation. The patient also had severe polyneuropathy with quadriparesis. Although most cases of EPP present in childhood, Henderson et al. (1995) reported a patient who presented at the age of 33 years and cited even older ages at presentation, namely 62 years (Fallon et al., 1989) and 69 years (Murphy et al., 1985). Whereas most EPP patients experience only a painful photosensitivity, a small number develop liver complications, including fatal liver damage, due to the accumulation of excessive amounts of protoporphyrin in the liver (Bloomer et al., 1975; Cripps et al., 1977; Bloomer, 1979). Gallstones pigmented with protoporphyrin have been reported. Both of the British patients of Magnus et al. (1961) and one of the patients of Haeger-Aronsen (1963) were operated on for gallstones at a relatively young age.
In a patient with erythropoietic protoporphyria, Lamoril et al. (1991) found compound heterozygosity for 2 different mutations in the FECH gene (612386.0001-612386.0002).
Henriksson et al. (1996) found a novel mutation in each of 4 Finnish erythropoietic ... In a patient with erythropoietic protoporphyria, Lamoril et al. (1991) found compound heterozygosity for 2 different mutations in the FECH gene (612386.0001-612386.0002). Henriksson et al. (1996) found a novel mutation in each of 4 Finnish erythropoietic protoporphyria families: 2 deletions and 2 point mutations. All 4 mutations resulted in a decreased steady-state level of the allelic transcript, since none of the mutations could be demonstrated by direct sequencing of the amplified cDNAs synthesized from total RNA extracted from the patients' lymphoblast cell lines. Henriksson et al. (1996) commented that, because the assays of ferrochelatase activity and erythrocyte protoporphyrin identified asymptomatic patients poorly, the DNA-based demonstration of a mutation is the only reliable way to screen individuals for the disease-associated mutation. Rufenacht et al. (1998) conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing gradient gel electrophoresis screening of FECH genomic DNA and direct sequencing. They characterized 20 different mutations, 15 of which were described for the first time, in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations was assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. Mutations leading to a null allele were a common feature among 3 EPP pedigrees with liver complications. Bloomer et al. (1998) focused on the gene mutations responsible for protoporphyria in patients requiring liver transplantation, i.e., those with the most severe phenotype. Mutations of the FECH gene were examined in 8 unrelated patients. RNA was prepared from liver and/or lymphoblasts, and specific reverse transcriptase-nested polymerase chain reactions were amplified and FECH cDNAs sequenced. Products shorter than normal resulted from an exon 3 deletion in 3 patients (612386.0008 and 612386.0009), exon 10 deletion in 2 (612386.0010 and 612386.0011), exon 2 deletion in 1 (612386.0012), and deletion of 5 nucleotides in exon 5 in 1 (612386.0013). Sequence of normal-sized products revealed no other mutations. Western blot showed a reduced quantity of normal-sized FECH protein in protoporphyria liver compared to normal liver. Liver FECH activity was reduced more than could be explained by the decrease in FECH protein. The gene mutations found in the most severe phenotype of protoporphyria shared the property of causing a major structural alteration in the FECH protein. Bloomer et al. (1998) suggested that the liver probably contributes to the overproduction of protoporphyrin that results in its own damage, and that the overproduction may increase as liver damage progresses. Gouya et al. (2002) showed that the mechanism for the low expression of FECH is the IVS3-48T-C transition (612386.0015). The presence of a C at position IVS3-48 was shown to cause 40% aberrantly spliced mRNA, compared with only 20% for the T allele. The reduced level of FECH was due to degradation of the aberrantly-spliced mRNA by the mechanism of nonsense-mediated mRNA decay. The C allele was present in 11% of French control individuals, and FECH activity in lymphocytes was significantly higher in individuals who were homozygous for T at the IVS3-48 position, compared with individuals who were heterozygous (C/T). Individuals who were homozygous for C showed the lowest FECH activity. Wiman et al. (2003) were among the first to evaluate the FECH mutations and the low-expression allele in their 26 apparently unrelated Swedish families with EPP. They found that all individuals carrying a mutated allele and IVS3-48C in trans to each other were affected by overt EPP. In a cross-sectional study of 223 EPP patients in the U.K., Holme et al. (2006) identified 6 EPP patients with palmar keratoderma; Holme et al. (2009) studied those 6 and 3 more such EPP patients and found that they represented a subtype of EPP characterized by seasonal palmar keratoderma, relatively low erythrocyte protoporphyrin concentrations, and recessive inheritance. None had evidence of liver dysfunction; 4 patients had neurologic abnormalities. The patients were compound heterozygous or homozygous for 9 different FECH mutations; prokaryotic expression predicted that FECH activities were 2.7% to 25% of normal (mean, 10.6%). Neither mutation type nor FECH activity provided an explanation for the unusual phenotype. Holme et al. (2009) concluded that palmar keratoderma is a clinical indicator of recessive EPP and represents a new subtype of EPP occurring in 38% of reported recessive EPP families, and suggested that patients with this phenotype may carry a lower risk of liver disease than other patients with recessive EPP. Of 11 unrelated Spanish patients with EPP, Herrero et al. (2007) found that 10 were compound heterozygous for the low-expression IVS3-48C allele in trans with another mutation in FECH, and 1 was homozygous for a novel A185T missense mutation (612386.0016).
Morais et al. (2011) stated that EPP has been reported worldwide, with a prevalence between 1 in 75,000 and 1 in 200,000.
Gouya et al. (2006) found that the frequency of the IVS3-48C allele (612386.0015) differed ... Morais et al. (2011) stated that EPP has been reported worldwide, with a prevalence between 1 in 75,000 and 1 in 200,000. Gouya et al. (2006) found that the frequency of the IVS3-48C allele (612386.0015) differed widely in the Japanese (43%), southeast Asian (31%), white French (11%), north African (2.7%), and black west African (less than 1%) populations. These differences could be related to the prevalence of EPP in these populations and may account for the absence of EPP in black subjects. Herrero et al. (2007) found that the frequency of the IVS3-48C allele among 180 nonporphyric Spanish individuals was 5.2%. Gouya et al. (2006) found that the phylogenetic origin of the IVS3-48C haplotypes strongly suggested that the IVS3-48C allele arose from a single recent mutational event. Estimation of the age of the IVS3-48C allele from haplotype data in white and Asian populations yielded an estimated age 3 to 4 times younger in the Japanese than in the white population, and this difference may be attributable to differing demographic histories or to positive selection for the IVS3-48C allele in the Asian population. Haplotype analysis suggested that the mutation occurred after the population had moved out of Africa.
Erythropoietic protoporphyria (EPP) should be suspected in individuals with the following findings: ...
DiagnosisErythropoietic protoporphyria (EPP) should be suspected in individuals with the following findings: Cutaneous photosensitivity, usually beginning in childhoodBurning, pain, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swellingBurning, itching, and intense pain; may occur without obvious skin damage Edema of the skin; may be diffuse and resemble angioneurotic edemaAbsent 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 transplantationDetection 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).TestingTable 1. Biochemical Characteristics of Erythropoietic Protoporphyria (EPP)View in own windowDeficient EnzymeEnzyme ActivityErythrocytesUrineStoolOtherFerrochelatase 1~10%-30% of normal 2Free protoporphyrin: increased 3, 4, 5, 6Protoporphyrins: not increasedProtoporphyrin: normal or increasedPlasma porphyrins: increased 7, 81. 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 View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFECHSequence analysis 2Sequence variants 3~91.5% ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions~8.5% 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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).3. 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.4. 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.5. See Whatley et al [2007].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in FECH.
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. ...
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].
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]....
Genotype-Phenotype CorrelationsThe 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.
Other causes of the erythropoietic protoporphyria (EPP) phenotype include the following: ...
Differential DiagnosisOther causes of the erythropoietic protoporphyria (EPP) phenotype include the following: Acquired causesPolymorphous light eruptionSolar urticariaDrug-induced photosensitivityAcquired 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)View in own windowDeficient EnzymeEnzyme ActivityErythrocytesUrineStoolOtherErythroid-specific 5-aminolevulinate synthase>200% 1 of normalFree protoporphyrin: zinc-chelated protoporphyrin= 90:10 to 50:50Protoporphyrins: Not detectableProtoporphyrin: Normal or increasedPlasma porphyrins: Increased1. Increased activity due to “gain-of-function” mutations in ALAS2 exon 11Possible 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with erythropoietic protoporphyria (EPP), the following evaluations are recommended: ...
ManagementEvaluations 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 ManifestationsAcute 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 hatsProtective 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 ComplicationsVitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency due to sun avoidance. Immunization for hepatitis A and B is recommendedSurveillanceAnnual 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 AvoidThe following are appropriate:Avoidance of sunlight and UV lightIn 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 RiskIf 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 ManagementPregnancy 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 InvestigationRecent 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFECH18q21.31Ferrochelatase, mitochondrialFECH homepage - Mendelian genesFECHData 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) View in own window 177000PROTOPORPHYRIA, ERYTHROPOIETIC; EPP 612386FERROCHELATASE; FECHNormal 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 VariantsView in own windowDNA Nucleotide Change (Conventional Nomenclature 1) Protein Amino Acid ChangeReference SequencesIVS3-48T>C 2(c.315-48T>C)Aberrant splicing of exon 4NM_000140.3 NP_000131.2See Quick Reference for an explanation of nomenclature. 1. Conventional mutation nomenclature, The Human Genome Variation Society (www.hgvs.org) 2. Variant designation that does not conform to current naming conventionsNormal 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.