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Variegate Porphyria

Synonym: Porphyria Variegata

, MD, MSc and , MD.

Author Information
, MD, MSc
Division of Gastroenterology and Hepatology
University of Alabama at Birmingham
Birmingham, Alabama
, MD
University of Texas Medical Branch
Galveston, Texas

Initial Posting: .

Summary

Clinical characteristics.

Variegate porphyria (VP) is a cutaneous porphyria (with chronic blistering skin lesions) and an acute porphyria (with severe episodic neurovisceral symptoms). The most common manifestation of VP is adult-onset cutaneous blistering lesions (subepidermal vesicles, bullae, and erosions that crust over and heal slowly) of sun-exposed skin, especially the hands and face. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. Cutaneous manifestations may improve in winter, and be less prevalent in northern regions and in dark-skinned individuals. Acute neurovisceral symptoms can occur any time after puberty, but less often in the elderly. Acute manifestations are highly variable, but may be similar from episode to episode in a patient with recurrent attacks; not all symptoms are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common symptoms are abdominal pain; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a primarily motor neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis. Psychiatric disturbances and autonomic neuropathy can also be observed. Acute attacks may be severe and are potentially fatal.

Diagnosis/testing.

No clinical features are specific for VP. It is important for all physicians, including primary physicians, to be aware of porphyrias and their variable features. The diagnosis is established by biochemical testing and confirmed by identification of a heterozygous mutation in PPOX, encoding the mitochondrial enzyme protoporphyrinogen oxidase (PPOX).

Management.

Treatment of manifestations: The first step in treating either acute neurovisceral attacks or cutaneous manifestations is to identify and remove exacerbating factors (see Agents/circumstances to avoid). Most acute neurovisceral attacks require hospital admission; the presence of seizures, motor neuropathy, and hyponatremia suggest severe disease that ideally should be managed in an ICU. Narcotic analgesics are usually required for pain. Ondansetron or a related drug can be used for nausea and vomiting; phenothiazines can be effective for nausea, agitation, and hallucinations.

Although mild attacks (without seizures, weakness or hyponatremia and not requiring narcotics) can sometimes be treated in an outpatient setting with glucose loading, most attacks require treatment with intravenous hemin.

Cutaneous symptoms are best managed by wearing protective clothing and avoiding exposure to sunlight. Symptoms may decrease when exacerbating factors are removed. No treatment is known to be effective in lowering porphyrin levels and reducing cutaneous symptoms. Analgesics may be needed for painful lesions and antibiotics for superimposed infection.

Prevention of primary manifestations: Acute neurovisceral attacks are less likely to occur if exacerbating factors are corrected or avoided. Recurrent premenstrual acute attacks can be prevented with GnRH analogues; weekly or biweekly hemin infusions to prevent frequent noncyclical attacks may be effective, but data are lacking. Prevention of the skin manifestations requires protection from sunlight.

Surveillance: Liver imaging at six-month intervals beginning at age 50 years in those who have experienced persistent elevations in porphobilinogen or porphyrins may detect early hepatocellular carcinoma.

Agents/circumstances to avoid: Exacerbating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated. Concomitant illnesses should be treated effectively using drugs that are considered safe whenever possible. Updated lists of safe and unsafe drugs are maintained at the Web sites of the American Porphyria Foundation and the European Porphyria Network.

Evaluation of relatives at risk: At-risk family members can be offered molecular genetic testing for the family-specific PPOX mutation to identify those who are heterozygous (for the purpose of counseling regarding appropriate use of drugs and avoidance of known exacerbating factors).

Pregnancy management: Exacerbations during pregnancy have been treated successfully with heme arginate and heme hydroxide (hematin); while neither preparation has been studied extensively during pregnancy, limited data suggest that treatment during pregnancy is unlikely to produce adverse fetal effects.

Genetic counseling.

VP is inherited in an autosomal dominant manner with reduced penetrance. De novo mutations are rare. Each child of an individual with VP has a 50% chance of inheriting the mutation; while offspring who inherit the mutation may or may not develop symptoms, most do not. Prenatal diagnosis for pregnancies at increased risk for VP is possible if the disease-causing mutation of an affected family member has been identified. Of note, the presence of a PPOX mutation does not predict whether – or at what age – an individual will become symptomatic.

Diagnosis

Variegate porphyria (VP) is a cutaneous porphyria (associated with characteristic chronic blistering skin lesions) and an acute porphyria (associated with acute severe episodic neurovisceral symptoms). VP is also classified as a hepatic porphyria, in which both the cutaneous and neurovisceral manifestations result from porphyrins and porphyrin precursors that originate in the liver.

No clinical features are specific for VP. The diagnosis is established by laboratory testing (Table 1) and confirmed by identification of a heterozygous mutation in PPOX, encoding the mitochondrial enzyme protoporphyrinogen oxidase (PPOX) [Anderson et al 2005] (Table 2).

The diagnosis of VP is suspected in individuals with the following clinical findings:

Cutaneous manifestations include chronic blistering photosensitivity, most commonly on the backs of the hands. Chronic features include blisters, milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. The skin lesions are identical to those of porphyria cutanea tarda (PCT) and several other porphyrias [Meissner et al 2003] (see Differential Diagnosis).

Neurovisceral symptoms most commonly include the following:

  • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present.
  • Constipation
  • Pain in the back, chest, and extremities
  • Anxiety
  • Seizures
  • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially and hyporeflexia as motor neuropathy progresses.
  • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [Anderson et al 2005].

Testing. Table 1 summarizes all the testing and test results relevant to the diagnosis of VP. All these biochemical features should be documented in a proband; however, for screening purposes a few selected tests are sufficient to detect or exclude VP and other porphyrias that cause the same symptoms.

  • When VP or any cutaneous porphyria is suspected as a cause of cutaneous findings without neurovisceral symptoms the recommended initial test is measurement of plasma porphyrins and plasma fluorescence scanning. Note: Although measurement of urine porphyrin is an alternative, elevations are found in many other medical conditions.
  • When VP or any acute porphyria is suspected as a cause of neurovisceral symptoms the recommended initial tests are measurements of urine porphobilinogen and total porphyrins.

When one of the initial tests is positive, additional biochemical testing (see Testing Strategy, Additional biochemical testing) is required to establish the specific type of porphyria, and for selection of the gene to be sequenced (see Testing Strategy) [Anderson et al 2005].

Table 1.

Biochemical Characteristics of Variegate Porphyria (VP)

Deficient EnzymeErythrocyte ProtoporphyrinUrine PBG and PorphyrinsStool PorphyrinsPlasma Porphyrins
ActiveAsxActiveAsxActiveAsxActiveAsx
Protoporphyrinogen oxidase (PPOX) 1, 2Nl or slightly ↑Nl or slightly ↑↑PBG and total porphyrins 3, 4, 5↑ or Nl PBG and total porphyrins; see footnote 6See footnote 7See footnote 8 ↑ See footnote 9↑ See footnotes 8 and 9

Active = symptomatic PPOX heterozygotes

Asx = asymptomatic PPOX heterozygotes

PBG = porphobilinogen

NI = not increased

1. This enzyme oxidizes protoporphyrinogen to protoporphyrin and its deficiency leads to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin

2. The enzyme assay is not needed for diagnostic purposes

3. PBG elevation can be detected rapidly and semi-quantitatively using a commercially available kit, which has replaced the obsolete Watson-Schwartz and Hoesch tests. Results of testing using the kit should be confirmed using a routine quantitative method such as that described by Mauzerall & Granick [1956], which also measures ALA. ALA is less elevated than PBG. Note: ALA is elevated in ALAD porphyria (ADP), in which PBG is normal or only slightly increased.

4. Active VP is suggested by a quantitative PBG that is substantially elevated

5. For screening, it is also useful to measure total porphyrins in the same urine sample, since levels of PBG can be less elevated in VP and HCP than in AIP and decrease to normal more rapidly. Note: Unlike a substantial increase in PBG, a substantial increase in urinary porphyrins does not document porphyria, as urinary porphyrins are increased in many other medical conditions, especially when the hepatobiliary system or bone marrow is affected.

6. PBG and total porphyrins may not be elevated in persons whose symptoms have resolved. If an acute porphyria is suspected to have caused past symptoms, full biochemical testing to include urinary ALA, PBG, and porphyrins, fecal porphyrins, and plasma porphyrins may be indicated.

7. Fecal porphyrins are markedly elevated in HCP and VP, whereas there is little or no elevation in AIP. The pattern of fecal porphyrins differentiates HCP and VP, with marked predominance of coproporphyrin III in HCP, and roughly equal elevations of coproporphyrin III and protoporphyrin in VP.

8. Measurement of fecal porphyrins and of plasma porphyrins are the most sensitive biochemical tests for detecting VP in the absence of symptoms.

9. A fluorescence scan of diluted plasma at neutral pH provides a fluorescence peak at wavelength 626 nm in VP that is highly sensitive and specific for this porphyria [Poh-Fitzpatrick 1980].

Molecular Genetic Testing

Gene. PPOX, encoding the mitochondrial enzyme protoporphyrinogen oxidase (PPOX; EC 1.3.3.4), is the only gene in which mutations are known to cause variegate porphyria [Brenner & Bloomer 1980, Whatley et al 1999, Whatley et al 2009].

Table 2.

Summary of Molecular Genetic Testing Used in Variegate Porphyria (VP)

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
PPOXSequence analysisSequence variants 496%-100% 5
Deletion / duplication analysis 6Exonic or whole-gene deletionsUnknown, none reported 7
Targeted mutation analysis 8p.Arg59TrpSee footnote 9
1.
2.

See Molecular Genetics for information on allelic variants.

3.

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

4.

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

5.
6.

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

7.

No exonic or whole-gene deletions or duplications involving PPOX have been reported to cause VP.

8.

Mutation panels may vary by laboratory.

9.

VP is especially common in South Africa due to a founder effect [Dean 1971], and about 95% of cases in that country are caused by the missense mutation p.Arg59Trp [Meissner et al 1996].

Testing Strategy

To confirm/establish the diagnosis of VP in a proband

Initial testing

  • Blistering cutaneous porphyrias (including VP). Measurement of porphyrins in plasma or urine
  • Acute porphyrias (including VP). Rapid screening test for elevations in urinary porphobilinogen (PBG)* and total porphyrins

    *Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack while further biochemical testing is being performed to determine the type of acute porphyria (see Differential Diagnosis). (2) If PBG is normal, δ-aminolevulinic acid and total porphyrins should be measured in the same urine sample, because it is important to consider other acute porphyrias including ADP in the differential diagnosis.

Additional biochemical testing. If one of the initial tests is abnormal, the following biochemical testing can establish the type of porphyria (in order to identify the gene in which mutations are most likely to be found by molecular genetic testing):

Note: The use of highly specialized laboratories with expertise on interpreting results as related to symptoms is recommended for this more advanced biochemical testing.

  • Expected biochemical findings in VP include elevations in urine ALA, PBG, and porphyrins (especially coproporphyrin III); plasma porphyrins (with a fluorescence peak at ~626 nm) [Poh-Fitzpatrick 1980]; and fecal porphyrins (markedly elevated and predominantly coproporphyrin III and protoporphyrin) (Table 1).
  • In hereditary coproporphyria, urine findings are the same, but plasma porphyrins are usually not elevated (fluorescence peak, if present, at ~619 nm), and fecal porphyrins are markedly elevated and predominantly coproporphyrin III.
  • In ALA dehydratase deficiency porphyria, urine ALA, coproporphyrin III, and erythrocyte zinc protoporphyrin are markedly elevated, but urine PBG is normal or slightly elevated.
  • In porphyria cutanea tarda, urine ALA may be slightly elevated; PBG is normal; urine and plasma porphyrins are substantially elevated with a predominance of uroporphyrin, hepta-, hexa- and pentacarboxylate porphyrins; plasma fluorescence scanning shows a peak at approximately 619 nm; and fecal porphyrins are variably increased with a complex pattern that includes isocoproporphyrins.
  • Unusual biochemical patterns may suggest double heterozygosity with deficiencies of two pathway enzymes.

Molecular genetic testing

  • In symptomatic probands. After the diagnosis of VP is established by biochemical methods, sequence analysis of PPOX should follow to identify the specific mutation.
  • In asymptomatic probands. If the medical history suggests that a past illness was caused by an acute porphyria but biochemical measurements are currently normal, molecular genetic testing of HMBS, CPOX, and PPOX may be considered. Of note, in individuals of white South African ancestry, targeted mutation analysis for the PPOX mutation p.Art59Trp may be considered as a first-tier test before sequence analysis of HMBS, CPOX, and PPOX.

Predictive testing for at-risk asymptomatic adult family members requires either prior identification of the disease-causing PPOX mutation in the family or, if molecular genetic testing is not possible, documentation of the biochemical test results that established the diagnosis of VP in an index case.

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

Clinical Characteristics

Clinical Description

Variegate porphyria (VP) is classified as both a cutaneous and an acute porphyria. It can present with chronic blistering cutaneous manifestations and/or acute attacks of neurovisceral manifestations that may become chronic.

Cutaneous manifestations. Chronic blistering photosensitivity, typically on the backs of the hands, is the most common manifestation of VP. The lesions result from sun exposure that activates porphyrins and makes the skin fragile and prone to blister formation. Lesions are located on sun-sensitive areas especially the hands and face. Sun-induced damage is not acute, so the role of sunlight is often not recognized. Cutaneous manifestations may improve in winter, and be less prevalent in northern regions and in dark-skinned individuals.

These and other manifestations of VP appear typically in adulthood and rarely before puberty.

The subepidermal vesicles, bullae, and erosions crust over and heal slowly. When blisters rupture they may become infected and painful.

Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur.

The skin manifestations are identical to those seen in porphyria cutanea tarda (PCT) and hereditary coproporphyria (HCP), and less severe than those seen in congenital erythropoietic porphyria (CEP) and hepatoerythropoietic porphyria (HEP). They contrast with the acute non-blistering photocutaneous manifestations of erythropoietic protoporphyria (EPP) (see Table 3.)

Neurovisceral symptoms can occur at any age after puberty as acute attacks which may become chronic. Symptoms are more common in women than men, and occur less often in the elderly. The frequency and severity of attacks vary considerably and are determined, in part, by exacerbating factors such as certain drugs, hormones, and nutritional factors [Anderson et al 2005]. The proportion of persons heterozygous for a PPOX mutation who experience acute attacks has decreased over the last three decades from about 30%-40% in the 1980s to 5%-10% currently [Hift & Meissner 2005].

The neurovisceral symptoms are identical to those in the other acute porphyrias (see Differential Diagnosis).

Acute manifestations vary. The most common symptoms are abdominal pain; constipation; pain in the back, chest and extremities; anxiety; seizures; and a predominantly motor peripheral neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis [Kauppinen & Mustajoki 1992, Meissner et al 2003, Anderson et al 2005, Hift & Meissner 2005]. Psychiatric disturbances and autonomic neuropathy can also be observed. Not all symptoms are present in a single episode and symptoms can vary from episode to episode; however, recurrent attacks are often similar. Acute attacks may be severe and are potentially fatal, but on average are less frequent and less severe than those observed in AIP [Hift & Meissner 2005].

Motor neuropathy usually manifests initially as proximal upper-extremity muscle weakness and can be difficult to detect. Hyperreflexia may be seen initially, followed by hyporeflexia as the motor neuropathy progresses. The motor neuropathy may be accompanied by sensory loss. Note: Motor neuropathy due to acute porphyrias is accompanied by little or no elevation of cerebrospinal fluid protein, which helps to differentiate it from the Landry Guillain-Barré syndrome [Anderson et al 2005].

Because abdominal pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present.

An acute attack can be fatal in the presence of severe manifestations including neuropathy, seizures, and respiratory compromise. If managed properly, the outcome of an acute attack is generally good. Neuropathy is reversible with recovery over a variable period typically over months and sometimes over several years.

Factors that predispose to acute attacks that are often identified include exposure to a harmful drug, alcohol, reduced dietary intake, or stress from an infection or other illness. Most harmful drugs are known to be inducers of hepatic δ-aminolevulinic acid synthase (ALAS) and hepatic cytochrome P450 enzymes (see Agents/Circumstances to Avoid). Pregnancy is usually well tolerated but can precipitate acute attacks in some women.

Physical findings such as tachycardia, hypertension, restlessness, and agitation result from autonomic neuropathy and increased circulating catecholamines.

Chronic pain may be a manifestation of VP and other acute porphyrias. Depression, which may be more difficult to link to the disease, is an important management issue.

Chronic liver abnormalities, particularly mild elevation of serum transaminases, are common. Risks for development of hepatocellular carcinoma and chronic renal disease are increased in VP (as well as in AIP and HCP). Hepatocellular carcinoma may develop especially after age 50 years in persons with persistent elevations in porphobilinogen and porphyrins.

Note: The speculation that VP affected King George III and perhaps others in the British royal family has been discounted [Peters 2011].

Genotype-Phenotype Correlations

PPOX mutations are generally severe and result in little or no enzyme activity; the residual approximately half-normal enzyme activity is a product of the normal allele. Therefore, different mutations are not associated with differences in disease severity [Whatley et al 1999, Whatley et al 2009].

Double heterozygosity for mutations in two different genes in the heme biosynthetic pathway. A patient with cutaneous manifestations initially diagnosed as HCP was found to be a double heterozygote for mutations in PPOX and CPOX after other family members were found to have biochemical features of VP [van Tuyll van Serooskerken et al 2011]. The phenotypes of such double heterozygotes vary but are not necessarily more severe than the phenotype associated with heterozygosity for a mutation in one gene alone, suggesting that individuals who are doubly heterozygous for mutations in genes causing two different types of acute porphyria may not be as rare as has been assumed. Such cases are suspected because of unusual biochemical patterns and, thus, are unlikely to be recognized without comprehensive biochemical testing [van Tuyll van Serooskerken et al 2011] that identifies a need for additional molecular genetic testing.

Penetrance

Mutant PPOX alleles that result in VP produce little or no functional enzyme; the approximately 50% of normal residual enzyme activity results primarily from the normal allele. Penetrance is reduced and may be increased by factors that increase the demand for hepatic heme synthesis.

The great majority of individuals who are heterozygous for a PPOX mutation are asymptomatic and are unlikely to be recognized or see a physician. In South Africa the frequency of acute attacks has decreased in recent decades. This may be due to less common use of harmful drugs such as barbiturates and sulfonamide antibiotics in clinical practice and perhaps better case recognition and information on how to avoid future attacks. VP now more commonly presents in South Africa with cutaneous rather than acute manifestations [Meissner et al 2003, Anderson et al 2005, Hift & Meissner 2005].

Nomenclature

Variegate porphyria (VP) and hereditary coproporphyria (HCP) were sometimes referred to as mixed porphyria, which is now an obsolete term.

VP has also been referred to as South African acute porphyria or protocoproporphyria.

In the past familial porphyria cutanea tarda (PCT) may not have been clearly differentiated from VP in some instances.

Prevalence

It is estimated that in the South African population three individuals per 1,000 are heterozygous for the PPOX mutation p.Arg59Trp, which is highly prevalent in that population [Meissner et al 1996, Meissner et al 2003].

VP is less prevalent than AIP in Europe and the United States with a prevalence of perhaps 0.5:100,000. In some parts of Europe such as Finland the prevalence is higher: 1.3:100,000 [Mustajoki 1980].

Differential Diagnosis

The porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in accumulation of a specific pattern of substrates (Figure 1). Because substrates of enzymes earlier and later in the pathway may also accumulate, the characteristic patterns are complex.

Figure 1.. Excretion profile of the hepatic porphyrias

Profile of heme precursor excretion for the types of hepatic porphyria.

Figure 1.

Excretion profile of the hepatic porphyrias

Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Mutations that decrease the function (more...)

In Table 3 the porphyrias are grouped by their principal clinical manifestations (neurovisceral or cutaneous) and the tissue origin of the excess production of pathway intermediates (liver [i.e., hepatic] or bone marrow [i.e., erythropoietic]).

‘Acute’ and ‘cutaneous’ are descriptive classifications and do not completely separate the porphyrias into two groups. For example, VP and HCP are both acute and cutaneous.

  • Porphyrias with neurologic manifestations are considered acute because the symptoms usually occur as discrete, severe episodes; however, chronic manifestations can develop. Susceptibility to exacerbating factors varies among individuals and over time, and is a feature of reduced penetrance. The four acute porphyrias are: ALA dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Only a few cases of ADP have been reported in the world literature.
  • Porphyrias with cutaneous manifestations include a number that cause chronic blistering skin lesions (i.e., VP as well as PCT, HCP, CEP, and HEP) and two that cause acute non-blistering photosensitivity (i.e., EPP and XLP).

Table 3.

Classification of the Porphyrias

Type of PorphyriaFindingsMode of Inheritance
Acute 1 Cutaneous
Hepatic
ADP 2+0AR
AIP+0AD
PCT0+AD 3
HCP++AD
VP++AD
Erythropoietic
CEP0+AR
EPP04AR
XLP04XL

ADP = ALA dehydratase deficiency porphyria

AIP = acute intermittent porphyria

HCP = hereditary coproporphyria

PCT = porphyria cutanea tarda

VP = variegate porphyria

CEP = congenital erythropoietic porphyria

EPP = erythropoietic protoporphyria

XLP= X-linked protoporphyria

0 = no symptoms

+ = mild to severe symptoms

1. Porphyrias with neurovisceral manifestations have been considered ‘acute’ in part because symptoms usually occur acutely as discrete, severe episodes; however, some affected individuals develop chronic manifestations and remain susceptible to exacerbating factors throughout their lives.

2. Classification of ADP as hepatic is uncertain

3. AD inheritance describes only the ~20% of persons with PCT who have a UROD mutation.

4. Photocutaneous manifestations are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP).

Acute neurologic porphyrias. The acute neurovisceral symptoms of VP are identical to those of the other acute porphyrias. Comprehensive biochemical analysis is always necessary to differentiate the four types of acute porphyria. Molecular genetic testing focusing on a particular gene (e.g., PPOX in VP) should then follow [Anderson et al 2005, Whatley et al 2009].

In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias, the entity most likely to be considered is acute ascending polyneuropathy, the Landry Guillain-Barré syndrome.

  • Abdominal pain, constipation, and tachycardia usually accompany the acute neurologic illness in the acute porphyrias but not in Landry Guillain-Barré syndrome.
  • CSF protein is usually normal in the acute porphyrias, but usually elevated in Landry Guillain-Barré syndrome.
  • Most importantly, urinary PBG is markedly elevated in the acute porphyrias especially when symptoms are present, but normal in Landry Guillain-Barré syndrome.

Chronic blistering photocutaneous porphyrias. VP can be readily differentiated from the following conditions by biochemical testing and ultimately confirmed by molecular genetic testing.

  • The blistering skin lesions of porphyria cutanea tarda (PCT), the most common human porphyria, are identical to those of VP. Because PCT is much more common than VP and responds to treatment that is not effective in VP, it is important to differentiate these disorders.
  • HCP is associated with such skin manifestations much less commonly than VP.
  • Blistering skin manifestations occur in AIP only when concurrent end-stage renal disease impairs porphyrin excretion and, thus, increases plasma porphyrin levels.
  • Cutaneous manifestations of CEP and HEP are also chronic and blistering but usually more severe than those of VP because circulating porphyrin levels are usually much higher (by an order of magnitude) than in PCT and VP. Although mild manifestations of CEP and HEP can be mistaken for those of VP, HCP, and PCT, these erythropoietic porphyrias are differentiated particularly by finding high levels of erythrocyte porphyrins.
  • Pseudoporphyria is a little-understood condition with cutaneous findings similar to PCT (and VP) but without significant porphyrin elevations.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with variegate porphyria (VP), the following evaluations are recommended:

  • Degree of elevations on plasma and urine porphyrins and urine PBG, if not determined at the time of diagnosis
  • Effects of VP on the skin, nervous system, liver, and kidneys
  • Contributions of medications, diet, and concurrent conditions on VP

Treatment of Manifestations

Neurovisceral Symptoms

Most acute neurovisceral attacks require hospital admission; patients with mild attacks (not requiring narcotic analgesics and without hyponatremia, seizures, or muscle weakness) are sometimes treated as outpatients. A rapid, thorough, and multidisciplinary evaluation is optimized by inpatient management.

As with other acute porphyrias, evaluation should include identification of exacerbating drugs and other precipitating factors. Harmful medications include barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Harmful medications should be discontinued.

Seizures, motor neuropathy, and hyponatremia suggest severe disease and should be managed in the ICU with adequate supportive treatment.

Narcotic analgesics are usually required for pain and ondansetron or a related drug for nausea and vomiting. A phenothiazine is also effective for nausea and for psychiatric symptoms (e.g., agitation, hallucinations) [Anderson et al 2005, Harper & Wahlin 2007].

Mild attacks (not requiring narcotics and without hyponatremia, seizures, or motor neuropathy) can be treated with glucose loading, but most attacks should be treated with intravenous hemin [Anderson et al 2005].

  • Note: ‘Hemin’ refers to the oxidized form of iron protoporphyrin IX, but is also the generic term for heme preparations used as intravenous therapies for acute porphyrias, such as lyophilized hematin (heme hydroxide) and heme arginate. When these hemin preparations are infused intravenously, the heme is bound to circulating albumin as heme albumin. The latter is taken up by hepatocytes and decreases the synthesis of hepatic ALAS1, the rate-controlling enzyme for heme synthesis in the liver.

Patients with acute attack should be carefully monitored for muscle weakness and respiratory impairment that may require ventilatory support.

Hyponatremia should be corrected slowly and seizures treated with medications that do not exacerbate porphyria.

Liver transplantation, which has been effective in persons with AIP with severe repeated acute attacks that respond poorly to medical therapy, is a consideration in VP [Dowman et al 2012].

Cutaneous Symptoms

Porphyrin levels may decrease and photosensitivity improve if exacerbating factors can be identified and removed. Otherwise there is no effective treatment that lowers porphyrin levels. Treatment with hemin may lower porphyrins in the short term only.

Patients should wear protective clothing and avoid exposure to sunlight.

Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Topical steroids are of little or no benefit.

Specific measures effective in the treatment of porphyria cutanea tarda (PCT) (i.e., phlebotomy and low-dose hydroxychloroquine or chloroquine) are not effective in the management of VP.

Prevention of Primary Manifestations

Acute attack

  • Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided.
  • Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with GnRH analogues [Anderson et al 1990].
  • Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking.

Photocutaneous. Prevention of the skin manifestations of VP requires protection from sunlight.

Prevention of Secondary Complications

Progression of renal disease may be prevented to some degree by controlling hypertension.

Surveillance

Hepatocellular carcinoma may develop especially after age 50 years in patients with acute porphyrias and persistent elevations in porphobilinogen or porphyrins; liver imaging at six-month intervals beginning at age 50 years may detect early lesions [Andant et al 2000, Schneider-Yin et al 2010].

Agents/Circumstances to Avoid

Precipitating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Updated lists are maintained at the Web sites of the American Porphyria Foundation and the European Porphyria Network.

Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated.

Evaluation of Relatives at Risk

At-risk family members can be offered molecular genetic testing for the family-specific PPOX mutation to identify PPOX heterozygotes for counseling regarding appropriate use of drugs and avoidance of known precipitating factors.

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Pregnancy Management

Pregnancy is usually well tolerated but some women heterozygous for a PPOX mutation may experience exacerbations.

Badminton & Deybach [2006] published an anecdotal report of successful treatment of several pregnant women experiencing attacks of VP or other acute porphyrias during pregnancy with hemin (in the form of heme arginate) without adverse fetal effect. They emphasize that interruption of pregnancy is almost never indicated for management of acute porphyria.

Experience with heme hydroxide is also limited but suggests no adverse effects during pregnancy [Isenschmid et al 1992]. As noted (see Treatment of Manifestations, Neurovisceral Symptoms, Note), hemin is delivered to tissues as heme albumin when administered as either heme arginate or heme hydroxide, and these preparations are expected to have similar safety profiles.

A fetus heterozygous for a PPOX mutation has a good prognosis, because most heterozygotes never develop symptoms and treatment for attacks is generally effective.

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

Variegate porphyria (VP) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

  • One parent of an individual with VP is expected to have the mutation that accounts for the disease in that family, and may or may not have had symptoms.
  • Rarely, VP may result from a de novo mutation.

Sibs of a proband

  • If a parent has the mutation, each sib has a 50% chance of inheriting the mutation. A sib with the mutation may or may not develop symptoms.
  • If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with VP has a 50% chance of inheriting the mutation. Offspring who inherit the mutation may or may not develop symptoms.

Other family members. If a parent has the disease-causing mutation, his or her family members are at risk of having the mutation. A person with the mutation may or may not develop symptoms.

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.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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:

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

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Note: The presence of a PPOX mutation detected by prenatal testing does not predict whether individuals will be symptomatic, or if they are, the age of onset or presentation of the disorder.

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

Requests for prenatal testing for conditions which (like VP) do not affect intellect and demonstrate reduced penetrance are not common. Further, most children who have inherited a disease-causing mutation remain asymptomatic, and attacks that could develop after puberty are generally responsive to treatment. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

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

Resources

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

  • American Porphyria Foundation (APF)
    4900 Woodway
    Suite 780
    Houston TX 77056-1837
    Phone: 866-273-3635 (toll-free); 713-266-9617
    Fax: 713-840-9552
    Email: porphyrus@aol.com
  • National Library of Medicine Genetics Home Reference
  • European Porphyria Network
    Email: contact@porphyria.eu
  • 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.

Variegate Porphyria: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
PPOX1q23​.3Protoporphyrinogen oxidasePPOX databasePPOX

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

Table B.

OMIM Entries for Variegate Porphyria (View All in OMIM)

176200PORPHYRIA VARIEGATA
600923PROTOPORPHYRINOGEN OXIDASE; PPOX

Normal allelic variants. PPOX comprises 13 exons (NM_001122764.1).

Pathogenic allelic variants. About 140 PPOX mutations have been identified in different families with variegate porphyria (VP).

VP is especially common in South Africa due to a founder effect, and about 95% cases in that country result from the missense mutation p.Arg59Trp.

Table 4.

Selected Pathogenic PPOX Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.175C>T 1p.Arg59TrpNM_001122764​.1
NP_001116236​.1
c.35T>Cp.Ile12Thr

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Protoporphyrinogen oxidase (PPOX) is an enzyme comprising 477 amino acids with a molecular weight of 51 kd. PPOX oxidizes protoporphyrinogen to protoporphyrin within mitochondria.

Abnormal gene product. Mutation of PPOX causes a partial deficiency of the mitochondrial enzyme protoporphyrinogen oxidase (PPOX), leading to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin and is excreted in the bile and stool.

During acute attacks individuals with VP consistently have elevation of δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), possibly as a result of inhibition of PBG deaminase by protoporphyrinogen.

References

Literature Cited

  1. Andant C, Puy H, Bogard C, Faivre J, Soulé JC, Nordmann Y, Deybach JC. Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors. J Hepatol. 2000;32:933–9. [PubMed: 10898313]
  2. Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–50. [PubMed: 15767622]
  3. Anderson KE, Spitz IM, Bardin CW, Kappas A. A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch Intern Med. 1990;150:1469–74. [PubMed: 2196028]
  4. Badminton MN, Deybach JC. Treatment of an acute attack of porphyria during pregnancy. Eur J Neurol. 2006;13:668–9. [PubMed: 16796597]
  5. Brenner DA, Bloomer JR. The enzymatic defect in variegate prophyria. Studies with human cultured skin fibroblasts. N Engl J Med. 1980;302:765–9. [PubMed: 7354807]
  6. Dean G. The Porphyrias: A Study of Inheritance and Environment. 2 ed. London, UK: Pitman Medical; 1971.
  7. Dowman JK, Gunson BK, Mirza DF, Bramhall SR, Badminton MN, Newsome PN. UK Liver Selection and Allocation Working Party.; Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl. 2012;18:195–200. [PMC free article: PMC3472026] [PubMed: 21618697]
  8. Frank J, McGrath J, Lam H, Graham RM, Hawk JL, Christiano AM. Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband. J Invest Dermatol. 1998;110:452–5. [PubMed: 9540991]
  9. Harper P, Wahlin S. Treatment options in acute porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria. Curr Treat Options Gastroenterol. 2007;10:444–55. [PubMed: 18221605]
  10. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore) 2005;84:48–60. [PubMed: 15643299]
  11. Isenschmid M, König C, Fässli C, Haenel A, Hänggi W, Schneider H. Acute intermittent porphyria in pregnancy: glucose or hematin therapy? Schweiz Med Wochenschr. 1992;122:1741–5. [PubMed: 1448679]
  12. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 1992;71:1–13. [PubMed: 1549056]
  13. Mauzerall D, Granick S. The occurrence and determination of δ-aminolevulinic acid and porphobilinogen in urine. J Biol Chem. 1956;219:435–46. [PubMed: 13295297]
  14. Meissner P, Hift RJ, Corrigall A. Variegate porphyria. In: Kadish KM, Smith K, Guilard R, eds. Porphyrin Handbook, Part II. Vol 14. San Diego, CA: Academic Press; 2003:93-120.
  15. Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG, Meissner DM, Kirsch RE, Dailey HA. A. R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet. 1996;13:95–7. [PubMed: 8673113]
  16. Mustajoki P. Variegate porphyria. Twelve years' experience in Finland. Q J Med. 1980;49:191–203. [PubMed: 7433635]
  17. Peters T. King George III, bipolar disorder, porphyria and lessons for historians. Clin Med. 2011;11:261–4. [PMC free article: PMC4953321] [PubMed: 21902081]
  18. Poh-Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol. 1980;116:543–7. [PubMed: 7377785]
  19. Schneider-Yin X, van Tuyll van Serooskerken AM, Went P, Tyblewski W, Poblete-Gutiérrez P, Minder EI, Frank J. Hepatocellular carcinoma in variegate porphyria: a serious complication. Acta Derm Venereol. 2010;90:512–5. [PubMed: 20814629]
  20. van Tuyll van Serooskerken AM, de Rooij FW, Edixhoven A, Bladergroen RS, Baron JM, Joussen S, Merk HF, Steijlen PM, Poblete-Gutiérrez P, te Velde K, Wilson JH, Koole RH, van Geel M, Frank J. Digenic inheritance of mutations in the coproporphyrinogen oxidase and protoporphyrinogen oxidase genes in a unique type of porphyria. J Invest Dermatol. 2011;131:2249–54. [PubMed: 21734717]
  21. Whatley SD, Mason NG, Woolf JR, Newcombe RG, Elder GH, Badminton MN. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem. 2009;55:1406–14. [PubMed: 19460837]
  22. Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, Elder GH, Deybach JC. Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet. 1999;65:984–94. [PMC free article: PMC1288269] [PubMed: 10486317]

Suggested Reading

  1. Kauppinen R, Timonen K. von und zu Fraunberg M, Laitinen E, Ahola H, Tenhunen R, Taketani S, Mustajoki P. Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect. J Invest Dermatol. 2001;116:610–3. [PubMed: 11286631]

Chapter Notes

Acknowledgments

This work is supported by the Porphyrias Consortium funded by the NIH/NIDDK and part of the Rare Diseases Clinical Research Network, and the American Porphyria Foundation.

Revision History

  • 14 February 2013 (me) Review posted live
  • 12 June 2012 (kea) Original submission
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