X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease ... X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease or gallstones (summary by Ducamp et al., 2013). For a phenotypic description of erythropoietic protoporphyria, see 177000.
In a subgroup of families with FECH (612386) mutation-negative protoporphyria, Whatley et al. (2008) studied 8 families in which at least 1 member had acute photosensitivity clinically indistinguishable from that seen in autosomal recessive erythropoietic protoporphyria (EPP; 177000). ... In a subgroup of families with FECH (612386) mutation-negative protoporphyria, Whatley et al. (2008) studied 8 families in which at least 1 member had acute photosensitivity clinically indistinguishable from that seen in autosomal recessive erythropoietic protoporphyria (EPP; 177000). Four families were of western European ancestry, and the others were of Jewish, North African, Indo-Asian, and Sudanese ancestry. In these 8 families, both sexes were affected. Patients had neither anemia nor iron overload. Instead there was some evidence of diminished iron stores, particularly in males. Five (17%) patients had overt liver disease, which was more common in males (0.008), and 1 obligate carrier was asymptomatic. These families showed an apparent X-linked pattern of inheritance with an absence of father-to-son transmission. Ducamp et al. (2013) reported 5 XLEPP patients from 4 unrelated families referred for a history of skin photosensitivity associated with increased levels of zinc- and metal-free protoporphyrin in erythrocytes. Two patients had elevated liver enzymes and 1 had gallstones. Most had evidence of iron deficiency, but only some patients had anemia.
The observation of apparent X linkage of EPP in 8 families prompted Whatley et al. (2008) to investigate 2 candidate genes on the X chromosome that are involved in heme formation, GATA1 (305371) and ALAS2 (301300). Protoporphyrin accumulation ... The observation of apparent X linkage of EPP in 8 families prompted Whatley et al. (2008) to investigate 2 candidate genes on the X chromosome that are involved in heme formation, GATA1 (305371) and ALAS2 (301300). Protoporphyrin accumulation segregated with an X chromosome haplotype defined by microsatellite markers around ALAS2 in 3 families. Sequencing of genomic DNA identified 2 different deletions in the last exon (exon 11) of ALAS2. The frameshifts produced by these deletions led to replacement or deletion of the approximately 20 C-terminal amino acids of the ALAS2 enzyme. These mutations segregated with photosensitivity (lod score 7.8) and were absent from 129 unrelated EPP patients (106 with dominant EPP, 23 with FECH mutation-negative EPP), and 100 normal chromosomes. The delAGTG mutation (301300.0015), present in 6 families, occurred on 5 different haplotypes, indicating that it had arisen on at least 5 separate occasions, whereas the 2 families with delAT (301300.0016), both from southwest England, had the same background haplotype and may have come from a single extended family. The ALAS2 gene encodes erythroid-specific mitochondrial aminolevulinate synthase-2, which catalyzes the first committed step of heme biosynthesis. Expression studies showed that both deletions markedly increased ALAS2 activity and that some of the 5-aminolevulinate (ALA) that was produced was further metabolized to porphyrin. Whatley et al. (2008) concluded that deletions in ALAS2 cause a theretofore unrecognized X-linked protoporphyria that, in contrast to autosomal dominant porphyrias, has close to 100% penetrance. In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, Ducamp et al. (2013) identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; 301300.0015) and the other 2 were novel (301300.0019 and 301300.0020). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. By generating a series of ALAS2 variants, Ducamp et al. (2013) found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein.
X-linked protoporphyria (XLP) should be suspected in individuals with the following findings: ...
DiagnosisClinical Diagnosis X-linked protoporphyria (XLP) should be suspected in individuals with the following findings: Cutaneous photosensitivity, usually beginning in childhoodBurning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swellingPainful symptoms; 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 complications; may be life threatening, necessitating liver and/or bone marrow transplantation (BMT)TestingDetection of markedly increased free erythrocyte protoporphyrin and zinc-chelated erythrocyte protoporphyrin is the most sensitive biochemical diagnostic test for XLP (Table 1). Identification of a gain-of-function mutation in ALAS2, the gene encoding erythroid specific 5-aminolevulinate synthase 2, confirms the diagnosis (Table 2).Table 1. Biochemical Characteristics of X-Linked Protoporphyria (XLP)View in own windowEnzyme DefectEnzyme ActivityErythrocytesUrineStoolOtherErythroid-specific 5-aminolevulinate synthase 2 (ALAS2)>100% of normal 1Free protoporphyrin/zinc-chelated protoporphyrin: ratio 90:30 to 50:50 2, 3, 4Protoporphyrins: not detectableProtoporphyrin: normal or increasedPlasma porphyrins: increased 51. Increased enzyme activity is due to ALAS2 gain-of-function mutations in exon 11. Note: Lymphocyte ferrochelatase activity is normal.2. 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.3. 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).4. In EPP, free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin (see Differential Diagnosis). 5. Plasma total porphyrins are increased in porphyrias with cutaneous manifestations including XLP. If plasma porphyrins are increased, the fluorescence emission spectrum of plasma porphyrins at neutral pH can be characteristic and can distinguish XLP and EPP from other porphyrias. The emission maximum in XLP and EPP occurs at 634 nm.Molecular Genetic Testing Gene. ALAS2, which encodes the enzyme erythroid specific 5-aminolevulinate synthase 2, is the only gene in which mutations are known to cause XLP. Clinical testingTable 2. Summary of Molecular Genetic Testing Used in X-Linked Protoporphyria View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability Affected MalesHeterozygous FemalesALAS2Sequence analysisSequence variants in exon 11 and in other coding and splicing regions 28/8 3, 48/8 3, 5Clinical Sequence analysis of select exonsSequence variants in exon 11 28/8 3, 48/8 3, 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.3. Eight out of eight families had one of two small deletion mutations in exon 11. See Molecular Genetics. 4. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.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 in a proband. For individuals with XLP-like photosensitivity, measurement of erythrocyte free and zinc-chelated protoporphyrin is the most sensitive and specific biochemical diagnostic test for XLP (Table 1). Note: It is essential to use an assay for erythrocyte protoporphyrin that distinguishes between free protoporphyrin and zinc-chelated protoporphyrin to differentiate XLP from EPP and several other conditions that may lead to elevation of erythrocyte protoporphyrins (see Table 1 footnotes 3 and 4).However, sequencing of exon 11 of ALAS2 is the most accurate diagnostic method, especially for the detection of asymptomatic heterozygous females who may have normal erythrocyte protoporphyrin levels.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing by sequence analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the ALAS2 disease-causing mutation in the family.Genetically Related (Allelic) Disorders X-linked sideroblastic anemia, the only other phenotype known to be associated with mutations in ALAS2, is caused by loss of function mutations throughout ALAS2.
The natural history of X-linked protoporphyria (XLP) is not well characterized as only eight families have been reported to date [Whatley et al 2008]. Although the cutaneous manifestations in males with XLP are similar to those of the autosomal recessive type of erythropoietic protoporphyria (EPP), the incidence of liver disease in XLP may be greater [Whatley et al 2008]. ...
Natural History The natural history of X-linked protoporphyria (XLP) is not well characterized as only eight families have been reported to date [Whatley et al 2008]. Although the cutaneous manifestations in males with XLP are similar to those of the autosomal recessive type of erythropoietic protoporphyria (EPP), the incidence of liver disease in XLP may be greater [Whatley et al 2008]. The phenotype of XLP in heterozygous females may range from as severe as in affected males to asymptomatic. Photosensitivity. Onset of photosensitivity is typically in infancy or childhood (with the first exposure to sun); in most individuals with XLP the photosensitivity remains for life. Most individuals with XLP develop acute cutaneous photosensitivity within five to 20 minutes following exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band, 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, which 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 hyper- or hypopigmentation, skin friability, and hirsutism. Unlike in other cutaneous porphyrias, blistering and scarring rarely occur. Hepatobiliary manifestations. Protoporphyrin is not excreted in the urine 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 back pain and severe abdominal pain (especially in the right upper quadrant). The information on XLP and liver disease is limited. Based on one published report, it appears that the risk for liver dysfunction in XLP (observed in 5/31 affected individuals) is higher than the risk in EPP [Whatley et al 2008]. The information presented below is based on experience of liver disease in EPP [Bloomer 1988].Gallstones composed in part of protoporphyrin may be symptomatic in individuals with XLP and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation. 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 XLP. Mild anemia with microcytosis and hypochromia or occasionally reticulocytosis can be seen; however, hemolysis is absent or mild. Vitamin D deficiency. Persons with XLP 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 XLP is sunlight.Pregnancy in EPP has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [Anderson et al 2001, Wahlin et al 2011a].
Erythropoietic protoporphyria, autosomal recessive(EPP) is caused by biallelic mutations in FECH (the gene encoding ferrochelatase). The photosensitivity and cutaneous manifestations are clinically indistinguishable from those seen in males with XLP. The only significant phenotypic difference is that only about 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. ...
Differential DiagnosisPolymorphous light eruptionSolar urticariaDrug induced photosensitivityErythropoietic protoporphyria, autosomal recessive (EPP) is caused by biallelic mutations in FECH (the gene encoding ferrochelatase). The photosensitivity and cutaneous manifestations are clinically indistinguishable from those seen in males with XLP. The only significant phenotypic difference is that only about 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. In EPP free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin (Table 3). Table 3. Biochemical Characteristics of Autosomal Recessive Erythropoietic Protoporphyria (EPP)View in own windowDeficient EnzymeEnzyme ActivityErythrocytesUrineStoolOtherFerrochelatase<30% of normal Protoporphyrin: >90% free, <10% zinc-chelatedProtoporphyrins: not increasedProtoporphyrin: normal or IncreasedPlasma porphyrins: IncreasedPossible additional genetic loci. It is presumed that additional loci may be responsible for the EPP phenotype (i.e., cutaneous photosensitivity and elevated erythrocyte protoporphyrins). Molecular epidemiology studies in the UK have identified biallelic FECH mutations or an ALAS2 mutation in only 94% of unrelated individuals 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 X-linked protoporphyria (XLP), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with X-linked protoporphyria (XLP), 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 suspectedMedical genetics consultationTreatment of ManifestationsAcute photosensitivity. There is no FDA-approved treatment specific for this disease; furthermore, there is no specific treatment for the acute photosensitivity.The pain is not responsive to narcotic analgesics.Although several treatments have been proposed, most have been tried only in a single patient or a small number of patients. The only effective current treatment is prevention of the painful attacks by avoidance of sun/light.Use of protective clothing including long sleeves, gloves, and wide brimmed hats is indicated.Protective tinted glass for cars and windows prevents exposure to UV light. Grey or smoke-colored filters provide only partial protection.Topical sunscreens are typically not useful; however, some tanning products containing creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent (e.g., zinc oxide) are often effective but are not cosmetically acceptable to all.Oral Lumitene™ (β-carotene) (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 beta-carotene has been used typically 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 beta-carotene, N-acetyl cysteine, and vitamin C [Minder et al 2009].Hepatic disease. 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, many transplant recipients experience a recurrence of the 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 in EPP [Holme et al 2007, Lyoumi et al 2007].Whatley et al [2008] reported some evidence of diminished iron stores in males with XLP; in one patient with iron deficiency, iron repletion decreased protoporphyrin accumulation and corrected the anemia.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 recommended.SurveillanceAnnual 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 such as an abdominal sonogram is 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 alcohol and 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 the ALAS2 mutation has been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with the disease-causing mutation 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 There is no information on pregnancy management in XLP. Based on experience with EPP pregnancy is unlikely to be complicated by XLP [Poh-Fitzpatrick 1997].Therapies Under InvestigationRecent clinical trials with a subcutaneous insertion of a biodegradable, slow-released α-melanocyte stimulating hormone analogue, afamelanotide, that increases pigmentation by increasing melanin appear promising for the treatment of EPP (see Differential Diagnosis) and XLP [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. 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. X-Linked Protoporphyria: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDALAS2Xp11.215-aminolevulinate synthase, erythroid-specific, mitochondrialALAS2 homepage - Mendelian genesALAS2Data 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 X-Linked Protoporphyria (View All in OMIM) View in own window 300752PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP 301300DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2Normal allelic variants. Alternatively spliced transcript variants of ALAS2 encode different isoforms (see Table A, Gene Symbol). The longest transcript has 11 exons. Pathologic allelic variantsEight families with XLP have been identified with one of two mutations (Table 4) [Whatley et al 2008]. Two small deletions, both in exon 11, introduce premature stop codons that predict truncation of the C-terminus of the enzyme. The congenital erythropoietic porphyria (CEP) phenotype may be modulated by sequence variations in ALAS2: a novel ALAS2 c.1757A>T variant in exon 11 was identified in a girl with severe CEP who was a compound heterozygote for two UROS mutations [To-Figueras et al 2011].Table 4. Selected ALAS2 Pathologic Allelic VariantView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1699_1700delATp.Met567Glufs*2NM_000032.4 NP_000023.2c.1706_1709delAGTGp.Glu569Glyfs*24c.1757A>T 1p.Tyr586PheSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Putative sequence variant that may modify the CEP phenotype [To-Figueras et al 2011]Normal gene product. ALAS2 encodes an erythroid-specific 5-aminolevulinate synthase; the normal isoform (NP_000023.2) has 587 amino acid residues, including a 49-amino acid transit peptide. The C-terminal amino acids encoded by exon 11 are believed to interact with the active site or other co-factors in a manner that regulates the activity of the enzyme.Abnormal gene product. Truncation of the C-terminal amino acids or marked alteration in structure that confers an inability to interact normally results in increased ALAS2 enzyme activity [Whatley et al 2008]. This leads to the systemic accumulation of free and zinc-chelated protoporphyrins, particularly in erythroid and hepatic cells. The rate of 5-aminolevulinic acid formation is increased to such an extent that insertion of iron into protoporphyrin by FECH becomes rate limiting for heme synthesis, resulting in the accumulation of protoporphyrins [Whatley et al 2008].