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X-Linked Protoporphyria

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

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Summary

Clinical characteristics.

X-linked protoporphyria (XLP) is characterized in affected males 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. Pain, 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. An unknown proportion of individuals with XLP develop liver disease. Except for those with advanced liver disease, life expectancy is not reduced. The phenotype in heterozygous females ranges from asymptomatic to as severe as affected males.

Diagnosis/testing.

Detection of markedly increased free erythrocyte protoporphyrin and zinc-chelated erythrocyte protoporphyrin is the most sensitive biochemical diagnostic test for XLP. Identification of pathogenic gain-of-function variants in ALAS2, the gene encoding erythroid specific 5-aminolevulinate synthase 2, 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. Currently the only effective treatment is prevention of the painful attacks by avoidance of sun/light (including the long-wave ultraviolet light 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 can be a life-saving measure in individuals with severe protoporphyric liver disease; combined bone marrow and liver transplantation is indicated in those with liver failure to prevent future damage to the allografts.

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 the ALAS2 pathogenic variant has been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with the pathogenic variant can benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction.

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

Genetic counseling.

XLP is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Women with an ALAS2 pathogenic variant have a 50% chance of transmitting the variant to each child. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

X-linked protoporphyria (XLP) should be suspected in individuals with the following findings:

  • Cutaneous photosensitivity, usually beginning in childhood
  • Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling
  • Painful symptoms; 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 complications; may be life threatening, necessitating liver and/or bone marrow transplantation (BMT)

Testing

Detection 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 pathogenic gain-of-function variant 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)

Enzyme DefectEnzyme ActivityErythrocytesUrineStoolOther
Erythroid-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 5
1.

Increased enzyme activity is due to ALAS2 pathogenic gain-of-function variants 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 pathogenic variants (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 pathogenic variants are known to cause XLP.

Table 2.

Molecular Genetic Testing Used in X-Linked Protoporphyria

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
Affected MalesHeterozygous Females
ALAS2Sequence analysisSequence variants in exon 11 and in other coding and splicing regions 48/8 5,68/8 5,7
Sequence analysis of select exonsSequence variants in exon 11 48/8 5,68/8 5,7
1.
2.

See Molecular Genetics for information on allelic variants.

3.

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

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Eight out of eight families had one of two small deletions in exon 11. See Molecular Genetics.

6.

Lack of amplification by PCR prior to sequence analysis can suggest a putative exon, multiexon, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

7.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

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 pathogenic variant 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 pathogenic variant 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 pathogenic variant in the family.

Clinical Characteristics

Clinical Description

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 2010, 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].

Pathophysiology

Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin that is excreted in bile and feces. 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 XLP is both free and zinc-chelated in approximately equal proportions, although wide variation has been reported.
  • 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 taken up by the endothelium of blood vessels.

The skin of persons with XLP 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, 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].

Individuals with autosomal recessive erythropoietic protoporphyria (EPP) seem predisposed to develop gallstones that are fluorescent and contain large quantities of protoporphyrin. While no information regarding gall stones in XLP is available, individuals with XLP are likely to be predisposed to cholelithiasis as well. 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. In contrast, 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, it 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

Because of the limited number of families known to have XLP, no genotype-phenotype correlations have been identified.

Penetrance

XLP appears to be 100% penetrant in males.

In heterozygous females, clinical variability is apparent and asymptomatic females have been reported [Whatley et al 2008, Di Pierro et al 2009].

Nomenclature

Although sometimes considered a synonym for XLP, the term "erythropoietic protoporphyria, X-linked dominant" is incorrect and should not be used: in all X-linked metabolic disorders the phenotype in heterozygous females can range from asymptomatic to as severe as that seen in affected males.

Prevalence

The prevalence of XLP is unknown.

  • Based on studies from the UK, it appears that XLP accounts for about 2% of individuals with the EPP phenotype [Whatley et al 2010].
  • Preliminary studies from the US indicate that the percentage of individuals with XLP is higher in the US [Balwani et al 2013].

Differential Diagnosis

  • Polymorphous light eruption
  • Solar urticaria
  • Drug induced photosensitivity

Erythropoietic protoporphyria, autosomal recessive (EPP) is caused by biallelic pathogenic variants 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)

Deficient EnzymeEnzyme ActivityErythrocytesUrineStoolOther
Ferrochelatase<30% of normalProtoporphyrin: >90% free, <10% zinc-chelatedProtoporphyrins: not increasedProtoporphyrin: normal or increasedPlasma porphyrins: increased

Possible 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 pathogenic variants or an ALAS2 pathogenic variant in only 94% of unrelated individuals with the EPP phenotype [Whatley et al 2010].

Management

Evaluations 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 suspected
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Acute 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. Gray 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 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 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 Avoid

The following are appropriate:

  • Avoidance of sunlight and UV light
  • In 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 Risk

If the ALAS2 pathogenic variant has been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with the pathogenic variant 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 Investigation

Recent clinical trials with a subcutaneous insertion of a biodegradable, slow-released α-melanocyte stimulating hormone analog, 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 III 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 II trials have been completed and Phase III trials are currently underway in order for the drug to receive FDA approval.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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

X-linked protoporphyria is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

  • The father of an affected male will not have the disease nor will he have the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male will have the pathogenic variant. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. No data on the frequency of germline mosaicism in XLP are available.
  • If a male is the only affected family member (i.e., a simplex case), the mother may have the pathogenic variant or the affected male may have a de novo pathogenic variant. No data on the frequency of de novo pathogenic variants in XLP are available.

Parents of a female proband. A female with XLP may have a de novo pathogenic variant or may have inherited an ALAS2 pathogenic variant from either parent; thus, if pedigree analysis reveals that the proband is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents (starting with her mother) to determine risks to family members.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
    • If the father of the proband has an ALAS2 pathogenic variant, he will transmit the variant to all of his daughters and none of his sons.
    • If the mother of the proband has an ALAS2 pathogenic variant, the chance of transmitting it in each pregnancy is 50% to both males and females. Sons who inherit the pathogenic variant will be affected. Daughters may or may not be affected (see Penetrance).
  • If a male proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low.
  • If a female proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low.

Offspring of a male proband. Affected males transmit the pathogenic variant to all of their daughters and none of their sons.

Offspring of a female proband. Women with an ALAS2 pathogenic variant have a 50% chance of transmitting the variant to each child.

Other family members of a proband. If a parent of the proband also has an ALAS2 pathogenic variant, his or her family members may be at risk of having the pathogenic variant and of being affected, depending on their genetic relationship to the proband.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

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 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 or at risk of having the ALAS2 pathogenic variant.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ALAS2 pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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. While decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.

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: contact@porphyria.eu
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Swedish Porphyria Patients' Association
    Karolinska Universitetssjukhuset
    Huddinge M 96
    Stockholm Stockholms Lan SE-141 86
    Sweden
    Phone: +46 8 711 56 09
    Email: porfyrisjukdomar@gmail.com
  • 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.

X-Linked Protoporphyria: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for X-Linked Protoporphyria (View All in OMIM)

300752PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP
301300DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2

Gene structure. Alternatively spliced transcript variants of ALAS2 encode different isoforms (see Table A, Gene). The longest transcript has 11 exons.

Pathogenic variants

Table 4.

Selected ALAS2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1699_1700delATp.Met567GlufsTer2NM_000032​.4
NP_000023​.2
c.1706_1709delAGTGp.Glu569GlyfsTer24
c.1757A>T 1p.Tyr586Phe

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

References

Literature Cited

  • Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:2991-3062.
  • Balwani M, Doheny D, Bishop DF, Nazarenko I, Yasuda M, Dailey HA, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Liu L, Desnick RJ. Loss-of-function ferrochelatase and gain-of-function erythroid 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med. 2013;19:26–35. [PMC free article: PMC3646094] [PubMed: 23364466]
  • Bloomer JR. The liver in protoporphyria. Hepatology. 1988;8:402–7. [PubMed: 3281889]
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Chapter Notes

Acknowledgments

The XLP contribution to GeneReviews was supported in part by the Porphyrias Consortium of the NIH-supported Rare Diseases Clinical Research Network (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

  • 14 February 2013 (me) Review posted live
  • 19 September 2012 (rd) Original submission
*

See Chapter Notes, Acknowledgments.

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