DiagnosisVariegate 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. ConstipationPain 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)View in own windowDeficient EnzymeErythrocyte ProtoporphyrinUrine PBG and PorphyrinsStool PorphyrinsPlasma PorphyrinsActiveAsxActiveAsxActiveAsxActiveAsxProtoporphyrinogen 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 9Active = symptomatic PPOX heterozygotesAsx = asymptomatic PPOX heterozygotesPBG = porphobilinogenNI = not increased1. This enzyme oxidizes protoporphyrinogen to protoporphyrin and its deficiency leads to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin2. 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)View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPPOXSequence analysisSequence variants 296%-100% 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsUnknown, none reported 5Targeted mutation analysis 6p.Arg59TrpSee footnote 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Whatley et al [2009]4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No exonic or whole-gene deletions or duplications involving PPOX have been reported to cause VP.6. Mutation panels may vary by laboratory.7. 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 probandInitial testingBlistering 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): Urine ALA, PBG, and porphyrinsPlasma porphyrins (including fluorescence scanning) [Poh-Fitzpatrick 1980]Erythrocyte porphyrins and fecal porphyrins [Anderson et al 2005, Whatley et al 2009]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 testingIn 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.Genetically Related (Allelic) Disorders PPOX homozygotes or compound heterozygotes have been described on rare occasion [Frank et al 1998]. In childhood they manifest neurologic findings including intellectual disability and/or seizures and cutaneous manifestations only. In these individuals one or both mutant alleles must produce some PPOX enzyme.}

Natural History 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 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].

Differential DiagnosisThe 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. FigureFigure 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 (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 PorphyriasView in own windowType of PorphyriaFindingsMode of InheritanceAcute ¹ Cutaneous HepaticADP ^{2+0ARAIP+0ADPCT0+AD 3HCP++ADVP++ADErythropoieticCEP0+AREPP0+ 4ARXLP0+ 4XLADP = ALA dehydratase deficiency porphyria AIP = acute intermittent porphyriaHCP = hereditary coproporphyriaPCT = porphyria cutanea tarda VP = variegate porphyriaCEP = congenital erythropoietic porphyriaEPP = erythropoietic protoporphyria XLP= X-linked protoporphyria0 = no symptoms+ = mild to severe symptoms1. 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 uncertain3. 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. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

ManagementEvaluations 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 diagnosisEffects of VP on the skin, nervous system, liver, and kidneysContributions of medications, diet, and concurrent conditions on VPTreatment of ManifestationsNeurovisceral 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 SymptomsPorphyrin 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 ManifestationsAcute attackAttacks 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 ComplicationsProgression of renal disease may be prevented to some degree by controlling hypertension. SurveillanceHepatocellular 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 AvoidPrecipitating 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 RiskAt-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 InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Variegate Porphyria: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPPOX1q23​.3Protoporphyrinogen oxidasePPOX homepage - Mendelian genesPPOXData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Variegate Porphyria (View All in OMIM) View in own window 176200PORPHYRIA VARIEGATA 600923PROTOPORPHYRINOGEN OXIDASE; PPOXNormal allelic variants. PPOX comprises 13 exons (NM_001122764.1). Pathologic 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 Pathologic PPOX Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.175C>T ^{1p.Arg59TrpNM_001122764​.1
NP_001116236​.1c.35T>Cp.Ile12ThrSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. rs121918324Normal 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.}