Erythropoietic Protoporphyria, Autosomal Recessive

Clinical characteristics.

Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.

Diagnosis/testing.

The diagnosis of EPP is established by detection of markedly increased free erythrocyte protoporphyrin and/or by the identification of biallelic pathogenic variants in FECH on molecular genetic testing.

Management.

Treatment of manifestations: Afamelanotide (Scenesse^®), a synthetic α-melanocyte stimulating hormone analog was approved for treatment of EPP by the European Medicines Agency in 2014 and is awaiting approval in the US by the FDA. This medication increases pain-free sun exposure and has improved quality of life in those with EPP. The phototoxic pain is not responsive to narcotic analgesics. Current management centers on prevention of the painful attacks by avoidance of sun/light (including the long-wave ultraviolet light sunlight that passes through window glass) through use of protective clothing (e.g., long sleeves, gloves, wide-brimmed hats, protective tinted glass for cars and windows). Although topical sunscreens are typically not useful, some tanning products containing creams that cause increased pigmentation may be helpful.

Severe liver complications are difficult to treat: cholestyramine and other porphyrin absorbents (to interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion) and plasmapheresis and intravenous hemin are sometimes beneficial. Liver transplantation may be required.

Prevention of primary manifestations. Sun avoidance.

Prevention of secondary complications: Vitamin D supplementation to prevent vitamin D insufficiency due to sun avoidance. Immunization for hepatitis A and B.

Surveillance: Monitoring of: hepatic function every six to 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: Avoid: sunlight and UV light; for those with hepatic dysfunction, drugs that may induce cholestasis (e.g., estrogens). For those with cholestatic liver failure, use of protective filters for artificial lights in the operating room to avoid phototoxic damage.

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

Genetic counseling.

EPP is inherited in an autosomal recessive manner. In about 96% of cases an affected individual inherits a loss-of-function FECH allele from one parent and a low-expression FECH allele from the other parent. In about 4% of cases, an affected individual has two loss-of-function FECH alleles. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Erythropoietic protoporphyria (EPP) should be suspected in individuals with the following clinical features and suggestive laboratory findings.

Clinical features

• Cutaneous photosensitivity, usually beginning in childhood
• Burning, tingling, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling
• Burning, itching, and intense pain; may occur without obvious skin damage
• Absent or sparse blisters 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 individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.)

Suggestive biochemical laboratory findings. Detection of markedly increased free erythrocyte protoporphyrin is the most sensitive and specific biochemical diagnostic test for EPP (see Table 1).

Note: It is important to evaluate by using an assay that distinguishes free protoporphyrin from zinc-chelated protoporphyrin, as several other conditions may lead to elevation of erythrocyte protoporphyrins (see Table 1, footnote 5).

Table 1.

Biochemical Characteristics of Erythropoietic Protoporphyria (EPP)

Establishing the Diagnosis

The diagnosis of EPP is established in a proband who has markedly increased free erythrocyte protoporphyrin and/or by the identification of biallelic pathogenic variants in FECH on molecular genetic testing (see Table 2).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of FECH is performed first, and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes FECH and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes FECH) fails to confirm a diagnosis in an individual with features of EPP and a significantly elevated erythrocyte protoporphyrin level. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Erythropoietic Protoporphyria

Note: Individuals with EPP have pathogenic variants in both FECH alleles.

• About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression pathogenic variant (c.315-48T>C; also known as 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" ‒ that is, 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 variant c.315-48T>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 pathogenic loss-of-function FECH variants are inherited, resulting in very low levels of functional ferrochelatase [Whatley et al 2010].

Clinical Description

Photosensitivity. Onset of photosensitivity is typically in infancy or childhood (with the first exposure to sun) and the photosensitivity remains for life.

• Most individuals with EPP develop acute cutaneous photosensitivity within 30 minutes after exposure to sun or ultraviolet 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.
• Affected individuals are also sensitive to sunlight that passes through window glass that does not block long-wave UVA or visible light.
• 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.
• Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [Anderson et al 2001, Wahlin et al 2011a].

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.
• Blistering was reported in 26% of individuals in one large series [Balwani et al 2017].
• Palmar keratoderma has been observed in some individuals with two loss-of-function FECH alleles (in contrast to one severe loss-of-function allele and the low-expression allele) [Holme et al 2009, Méndez et al 2009, 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 of these 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 including 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].
• The risk of liver disease appears to be related to higher protoporphyrin levels.

Hematologic manifestations. 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 2010, Wahlin et al 2011a].

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

Pathophysiology

The deficient activity (<30% of normal) of ferrochelatase results in EPP.

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

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

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

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

As noted, individuals with EPP appear to be predisposed to developing gallstones that are fluorescent and contain large quantities of protoporphyrin. In one series, approximately 22% of individuals with EPP had a known history of gallstones [Balwani et al 2017]. This and other hepatobiliary complications relate to uptake and excretion of protoporphyrin by the liver [Bloomer 1988]. This dicarboxyl porphyrin is not soluble in aqueous solution and is therefore not excreted in urine.

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

Genotype-Phenotype Correlations

About 96% of affected individuals are compound heterozygotes for a loss-of-function variant that markedly decreases ferrochelatase (FECH) activity and a second low-expression pathogenic variant which also decreases the FECH activity by about 50%.

Persons with low residual activity may have a more severe clinical presentation. Palmar keratoderma was reported in persons with two loss-of-function FECH variants [Holme et al 2009, Méndez et al 2009, Minder et al 2010]. Some reports have indicated that null variants in FECH may be associated with liver complications [Minder et al 2002],

Individuals with EPP with pathogenic missense variants have significantly lower median erythrocyte protoporphyrin levels than those with deletions or nonsense or consensus splice site variants. The greater the level of erythrocyte protoporphyrin, the more likely that the patient will be more severely affected, characterized by decreased sun tolerance and increased risk of liver dysfunction [Balwani et al 2017].

Penetrance

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

Nomenclature

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

Prevalence

EPP is the third most common porphyria, with an estimated incidence of two to five in 1,000,000; it is the most common porphyria in children.

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

EPP has been described worldwide. The prevalence of EPP may vary based on the population allele frequency of the low-expression c.315-48T>C allele, which ranges from approximately 1%-3% in Africans to approximately 43% in Japanese.

Evaluations Following Initial Diagnosis

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

• Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing
• Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Acute photosensitivity. Afamelanotide (Scenesse®), a synthetic α-melanocyte-stimulating hormone analog was approved for treatment of EPP by the European Medicines Agency in 2014. The drug is administered through a subcutaneously inserted bioresorbable implant which results in increased pigmentation due to an increase in eumelanin. Phase III clinical trials in the US and Europe showed an increase in pain-free sun exposure and improved quality of life in individuals with EPP. In the United States, the drug is pending FDA approval.

The phototoxic pain is not responsive to narcotic analgesics.

Current management centers on prevention of the painful attacks by avoidance of sun/light, including the long-wave ultraviolet light sunlight that passes through window glass:

• Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
• Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke-colored filters provide only partial protection.
• Tanning products. Some tanning creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent are often effective but are not cosmetically acceptable to all. Topical sunscreens are typically not useful.
• β-carotene. Oral Lumitene™ (120-180 mg/dL) may improve tolerance to sunlight in some patients 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 dose of Lumitene depends on age, ranging from two to ten 30-mg capsules per day and usually started six to eight weeks before summer. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, there are currently no data to support its efficacy [Minder et al 2009].

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

• 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 Primary Manifestations

Sun avoidance is the only effective means of preventing primary manifestations.

Prevention of Secondary Complications

Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency as a result of to sun avoidance.

Immunization for hepatitis A and B is recommended.

Surveillance

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

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

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

Agents/Circumstances to Avoid

The following are appropriate:

• Avoidance of sunlight and UV light
• In patients with hepatic dysfunction, avoidance of drugs that 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

It is appropriate to evaluate at-risk family members as newborns or infants in order to identify as early as possible those who would benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction.

Evaluations can include the following:

• Molecular genetic testing if both FECH pathogenic variants in the family are known
• Biochemical testing to detect markedly increased free erythrocyte protoporphyrin if the pathogenic variants in the family are not known

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

Pregnancy Management

Pregnancy is not complicated by EPP. There may be some improvement in photosensitivity during pregnancy as well as a reduction in protoporphyrin levels [Poh-Fitzpatrick 1997, Heerfordt & Wulf 2016].

Therapies Under Investigation

Phase III clinical trials from the US and Europe with a subcutaneous insertion of a biodegradable, slow-released α-melanocyte-stimulating hormone analog, afamelanotide (Scenesse^®), which increases pigmentation by increasing melanin, showed increased pain-free sun exposure and improved quality of life in those with EPP [Harms et al 2009, Minder et al 2009, Minder 2010, Langendonk et al 2015]. A long-term observational study of 115 individuals receiving Scenesse^® for up to eight years showed improved quality of life and high compliance with the drug [Biolcati et al 2015].

• Scenesse^® is currently approved for use in patients with EPP in the European Union.
• In the United States, the drug is pending FDA review.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

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

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers) for either a FECH loss-of-function allele or the common low-expression FECH allele.
  • Most often one parent transmits the loss-of-function FECH allele and the other transmits the common low-expression FECH allele to their affected child.
  • In about 4% of couples, both parents transmit a loss-of-function FECH allele to their affected child.
• Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) and sibs who inherit two low-expression alleles are asymptomatic.

Offspring of a proband

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

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a loss of function FECH allele or low-expression FECH allele.

Carrier Detection

Carrier testing for at-risk family members requires prior identification of the FECH pathogenic variants in the family.

Biochemical testing is not used for carrier detection.

Related Genetic Counseling Issues

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

Family planning

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

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the FECH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Biochemical testing is not used for prenatal diagnosis.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Acknowledgments

The EPP 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

• 7 September 2017 (ha) Comprehensive update posted live
• 16 October 2014 (me) Comprehensive updated posted live
• 27 September 2012 (me) Review posted live
• 10 April 2012 (rd) Original submission