Alternative titles; symbols
SNOMEDCT: 58275005; ORPHA: 79473; DO: 4346;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.3 | Variegate porphyria | 176200 | Autosomal dominant | 3 | PPOX | 600923 |
A number sign (#) is used with this entry because of evidence that variegate porphyria (VP) is caused by heterozygous mutation in the gene encoding protoporphyrinogen oxidase (PPOX; 600923) on chromosome 1q23.
Biallelic mutation in the PPOX gene causes a childhood-onset form of variegate porphyria (VPCO; 620483).
Variegate porphyria (VP) is characterized by cutaneous manifestations, including increased photosensitivity, blistering, skin fragility with chronic scarring of sun-exposed areas, and postinflammatory hyperpigmentation. Acute exacerbations of VP include abdominal pain, the passage of dark urine, and neuropsychiatric symptoms that characterize the acute hepatic porphyrias, such as bulbar paralysis, quadriplegia, motor neuropathy, and weakness of the limbs. VP is inherited as an autosomal dominant trait with incomplete penetrance. Clinical manifestations do not usually present before puberty, and PPOX activity is decreased by about 50% (summary by Frank et al., 1998).
Adults with variegate porphyria show a variable picture of skin symptoms, including hyperpigmentation and hypertrichosis, associated with acute attacks like those of acute intermittent porphyria (176000). Attacks may be protracted and followed by prolonged disability. Attacks are often drug-induced and show the classic neuropathic symptoms and signs, such as abdominal pain, constipation, tachycardia and hypertension, and muscular paralysis and sensory disturbances; disorientation and frank psychosis may be conspicuous features. The condition is characterized by elevated fecal levels of protoporphyrin and coproporphyrin at all times, with increased urine porphyrins at times, and an increase in urinary levels of the porphyrin precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) during the acute attack (Dean, 1972; Mustajoki, 1978; Meyer and Schmid, 1978). Iron overload is a well-established precipitating or aggravating factor in porphyria variegata.
Frank et al. (1998) reported 2 unrelated patients with variegate porphyria and mutation in the PPOX gene. Proband 1 was a 57-year-old woman of German ancestry who developed a life-threatening acute porphyric attack with paralysis at around 30 years of age. At that time the diagnosis of acute intermittent porphyria was rendered on the basis of clinical and biochemical findings. Thereafter she experienced recurrent colicky abdominal pain, vomiting, and mental confusion. Upon sun exposure, small blisters developed on the forearms and the back of the hands that left chronic hyperpigmented scars. The diagnosis of variegate porphyria was made on the basis of the cutaneous symptoms and porphyrin analysis of the feces. Proband 2 was a 38-year-old woman of Armenian and North American ancestry who was diagnosed with variegate porphyria on the basis of clinical and biochemical findings; no clinical details were provided.
Collantes-Rodriguez et al. (2020) reported a 25-year-old Spanish man with a 5-year history of blistering skin lesions on the backs of his hands, associated with hyperpigmentation and hypertrichosis and exacerbation in spring and summer. He had no systemic symptoms. There was a maternal family history of similar lesions without associated systemic symptoms. Biochemical analysis showed elevated uroporphyrin and the presence of coproporphyrin and protoporphyrin in the proband's feces.
The basic defect appears to be reduction in the activity of the enzyme protoporphyrinogen oxidase to approximately 50% of the normal level as determined in skin fibroblasts (Brenner and Bloomer, 1980) and presumably in other tissues, especially liver. This enzymopathy is unusual in being the effect of a single gene dose, rather than requiring a double dose for its expression. Several other genetic porphyrias share this effect; see 121300, 176000, and 176100.
Logan et al. (1991) noted that biochemical confirmation of the diagnosis of variegate porphyria can be difficult, particularly in patients without neurologic dysfunction at the time of testing. Levels of porphyrin in the stool may be normal because food and bacterial metabolism in the intestine contribute to the porphyrin content of the feces and may obscure the differences in levels between normal and affected persons. To overcome this shortcoming, Logan et al. (1991) measured porphyrin levels in the bile and found considerably greater differences in bile levels than in fecal levels in patients and normals. Kushner (1991) reviewed the laboratory diagnosis of the porphyrias.
Management of porphyria consists primarily of avoidance of porphyrinogenic agents and protection for photosensitive skin (Kushner, 1991).
Cochrane and Goldberg (1968) reported studies of an extensive kindred of which the first author was a member. Children and asymptomatic adults showed the chemical features without manifest disease, but allowed the demonstration that porphyria variegata segregates is an autosomal dominant trait, with manifestation in about one half of affected adults (Cochrane and Goldberg, 1968; Dean, 1972; Hamnstrom et al., 1967; Fromke et al., 1978; Husquinet et al., 1978).
VP is usually inherited as an autosomal dominant trait with incomplete penetrance (Frank et al., 1998).
Porphyria variegata was observed in 3 families in Sweden by Hamnstrom et al. (1967). No genealogic connection with any of the 600 known cases of acute intermittent porphyria could be shown.
Dean (1972) described in an engaging manner his studies of porphyria in South Africa and comparative studies in Sweden, Holland, Turkey, and elsewhere. The high frequency of the gene for porphyria variegata in South Africa is a cardinal example of founder effect. Dean (1972) estimated that about 8,000 persons in South Africa were suffering from porphyria inherited from either Gerrit Jansz, a Dutch settler in the Cape, or his wife, Ariaantje Jacobs, who was 1 of 8 sent from an orphanage in Rotterdam to provide wives for Dutch settlers in the Cape. He estimated, furthermore, that 1 million of 3 million whites are descendants of 40 original settlers and their wives, a 12,000-fold increase. Stine and Smith (1990) calculated a coefficient of selection between 0.07 and 0.02 for the porphyria variegata gene in the Afrikaner population of South Africa. Jenkins (1990) gave a comprehensive review of medical genetics in South Africa; porphyria variegata was included in a listing of inherited conditions of unusual prevalence among some southern African populations. (See 600923.0003 for the probable founder gene defect associated causally with VP in South Africa.)
Porphyria variegata is also frequent in Finland (Mustajoki, 1980), where prevalence was estimated to be 1.3 per 100,000. Of 57 patients in 9 families, 18 had had acute attacks. During an average of 5.7 years' follow-up, only 2 of 48 patients had symptoms, which were temporary and acute. The longevity of gene carriers did not differ from that of the general population. Skin fragility occurred in 45% of patients and was usually mild. Mustajoki (1980) concluded that variegate porphyria might be commoner than suspected, noting that only half of patients in temperate and cold climates have skin symptoms, the risk of developing an acute attack is low, and some adult patients excrete normal or only slightly abnormal amounts of porphyrin. Of 57 patients in 9 families, 18 had had acute attacks, but the longevity of gene carriers did not differ from that of the general population. Skin fragility was usually mild.
Bissbort et al. (1988) demonstrated linkage between VP and alpha-1-antitrypsin (107400); the maximum lod score from male meioses was 4.33 at theta = 0.04, and from both sexes combined, 3.56 at theta = 0.12. In pedigrees triply informative for VP, PI and the Gm polymorphism, VP and PI cosegregated separately from Gm. These findings argued in favor of either gene order VP--PI--IGHC or PI--VP--IGHC.
Taketani et al. (1995) showed by Southern blotting of human genomic DNA that there is a single copy of the PPOX gene, and by fluorescence in situ hybridization they mapped the gene to 1q22 (see also 600923). The reason for the discrepancy between linkage mapping of variegate porphyria to chromosome 14 by Bissbort et al. (1988) and this location of the gene by fluorescence in situ hybridization is unexplained; however, Taketani et al. (1995) suggested that it is possible that an additional gene product on chromosome 14 may interact with PPOX protein to maintain the normal enzyme activity or to affect expression of the PPOX gene (thus accounting for the findings of Bissbort et al. (1988) referred to earlier).
Roberts et al. (1995) likewise mapped the PPOX gene to chromosome 1 (1q23) and showed that the clinical disorder variegate porphyria is linked to microsatellite and other markers in the region 1q21-q23. They concluded that the evidence spoke against locus heterogeneity in VP.
Deybach et al. (1996) investigated the molecular defect responsible for VP by sequencing the coding portions of the PPOX gene in 4 patients in 3 unrelated families of French Caucasian origin. In 1 patient, insertion of G at position 1022 of the cDNA produced a frameshift resulting in a premature stop codon (600923.0001). In 3 other patients from 2 unrelated families, they found a missense mutation leading to substitution of arginine for glycine (G232R) in exon 7 (600923.0002). In 1 of the latter families, consisting of 14 members over 3 generations, they demonstrated the cosegregation of the G232R mutation with deficient PPOX activity. This was the first report of mutations in patients with VP and supported the conclusion that PPOX gene defects cause variegate porphyria.
Meissner et al. (1996) described an arg59-to-trp (R59W) mutation in the PPOX gene (600923.0003) in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with protoporphyrinogen oxidase deficiency. Since at least one of these families could be shown to be descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa.
Warnich et al. (1996) identified the R59W mutation in 15 of 17 South African patients with variegate porphyria. This mutation was shown to create a StyI restriction site and was found to be associated with C(26)-C(150), 1 of 4 potential haplotypes defined by 2 polymorphisms in exon 1 of the PPOX gene. Warnich et al. (1996) reported that these data supported the founder hypothesis for variegate porphyria in South Africa. In 1 of 17 patients there was an exon 2 mutation (H20P; 600923.0005). This mutation was associated with the same exon 1 polymorphism haplotype as the R59W mutation. An exon 6 mutation, R168C (600923.0004), was identified in 1 patient; this mutation abolished a DsaI restriction site in genomic DNA of affected individuals and was shown to be associated with a different haplotype for the exon 1 polymorphism, A(26)-C(150).
In 2 unrelated women with variegate porphyria, Frank et al. (1998) analyzed exon 6 of the PPOX gene and identified heterozygosity for the same missense mutation (R168H; 600923.0006). Segregation analysis in the family of proband 1 revealed that her unaffected son also carried the R168H variant, indicating incomplete penetrance; relatives of proband 2 were unavailable for study. The mutation was not found in 50 unrelated controls.
De Villiers et al. (1999) identified a South African patient with severe VP carrying the R59W mutation who was also a compound heterozygote for the HFE mutations his63 to asp (235200.0002) and gln127 to his (235200.0007). De Villiers et al. (1999) concluded that the population screening approach used in their study supported previous data on the involvement of the HFE gene in the porphyria phenotype.
Wiman et al. (2003) stated that approximately 80 individuals from 28 apparently unrelated families had been diagnosed with VP in Sweden. Genetic analysis of the PPOX gene in 17 of these families identified 10 different mutations, only 1 of which had previously been reported. None was found in 50 Swedish controls. Mutation analysis in family members revealed 2 adults and 4 children who were silent carriers of the VP trait.
Borrero Corte et al. (2019) sequenced the PPOX gene in 8 unrelated Spanish patients with variegate porphyria, 4 of whom had only cutaneous photosensitivity, 3 of whom experienced only acute symptoms, and 1 of whom had both. The authors identified heterozygosity for known VP-associated mutations in all patients (see, e.g., 600923.0006). No genotype/phenotype correlations were observed.
In a 25-year-old Spanish man with a 5-year history of cutaneous photosensitivity and a biochemical profile consistent with VP, Collantes-Rodriguez et al. (2020) sequenced the PPOX gene and identified 2 missense mutations in cis, a G41C and W42R substitution, both at highly conserved residues. His similarly affected mother also carried both variants; his unaffected father did not carry either variant.
Von und zu Fraunberg et al. (2002) investigated clinical and biochemical characteristics and genotype-phenotype correlations for 3 common PPOX mutations in Finnish patients with VP identified during a period of 35 years. Of the 103 patients studied, 52% experienced clinical symptoms: 40% had photosensitivity, 27% had acute attacks, and 14% had both manifestations. The proportion of patients with acute attacks decreased from 38% to 14% in patients diagnosed before and after 1980. Of 90 patients genotyped for the common Finnish mutations in PPOX, those with the I12T mutation had no photosensitivity, few acute attacks (8%), and milder biochemical abnormalities. Risk of skin symptoms and acute attacks diminished with normal adult fecal protoporphyrin excretion, but increased with an increased urine excretion of coproporphyrin to the point where all patients with greater than 1,000 nmol/day excretion had skin symptoms, acute attacks, or both.
Macalpine et al. (1968) suggested that George III suffered from porphyria and that the disease can be traced back to Mary Queen of Scots, thus starting a spirited controversy. Many authorities do not accept the speculation. Although the malady of George III is indistinguishable retrospectively from acute intermittent porphyria, supposed dermatologic and other manifestations in members of the family suggest that the royal porphyria, if any, was the variegate type.
Jenkins (1996) discussed the madness of King George III and also the history of 'the South African malady.' Alan Bennett's highly successful play and film 'The Madness of King George' reawakened debate on whether the sovereign suffered from porphyria. Ida Macalpine and Richard Hunter, who first formulated the retrospective diagnosis (Macalpine and Hunter, 1966), were eminent psychiatrists and were authors of a history of psychiatry (Hunter and Macalpine, 1963). Warren et al. (1996) reviewed the history of the suggested diagnosis and its possible influence on history through the members of the royal family.
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Borrero Corte, M. J., Jara Rubio, F., Moran Jimenez, M. J., Diaz Diaz, S., Castelbon Fernandez, F. J., Garcia Pastor, I., Enriquez de Salamanca, R., Mendez, M. Molecular analysis of 19 Spanish patients with mixed porphyrias. Europ. J. Med. Genet. 62: 103589, 2019. [PubMed: 30476629] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.023]
Brenner, D. A., Bloomer, J. R. The enzymatic defect in variegate porphyria: studies with human cultured skin fibroblasts. New Eng. J. Med. 302: 765-769, 1980. [PubMed: 7354807] [Full Text: https://doi.org/10.1056/NEJM198004033021401]
Cochrane, A. L., Goldberg, A. A study of faecal porphyrin levels in a large family. Ann. Hum. Genet. 32: 195-208, 1968. [PubMed: 5715631] [Full Text: https://doi.org/10.1111/j.1469-1809.1968.tb00064.x]
Collantes-Rodriguez, C., de la Varga-Martinez, R., Villegas-Romero, I., Jimenez-Gallo, D., Linares-Barrios, M., Mora-Lopez, F. Two new mutations in the PPOX gene in a patient with variegate porphyria. J. Dtsch. Derm. Ges. 18: 381-383, 2020. [PubMed: 32247286] [Full Text: https://doi.org/10.1111/ddg.14079]
de Villiers, J. N. P., Hillermann, R., Loubser, L., Kotze, M. J. Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Hum. Molec. Genet. 8: 1517-1522, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1817 only, 1999. [PubMed: 10401000] [Full Text: https://doi.org/10.1093/hmg/8.8.1517]
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