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PubMed1996

Mapping of the variegate porphyria (VP) gene: contradictory evidence for linkage between VP and microsatellite markers at chromosome 14q32.

The gene for variegate porphyria (VP), an autosomal dominant disease with a high prevalance in South Africa, evidently due to a founder effect, was previously mapped to chromosome 14q32. In the current study this localization was evaluated by linkage and haplotype analyses using microsatellite markers spanning a region of more than 20 cM on chromosome 14q32. In many recent studies linkage disequilibrium between disease and marker loci has been utilized to map genes in founder populations, but we could not find any association between VP and the markers used in this study. Our data suggest that the allocation of VP to chromosome 14q32 may be incorrect.

Chromosome Mapping↗
PubMed2004

Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard.

BACKGROUND: Variegate porphyria (VP) is the autosomal dominant disorder associated with deficiency of the enzyme protoporphyrinogen oxidase (PPOX). Plasma fluorescence scanning has been reported to be a more sensitive test for VP than traditional fecal chromatography. Previous comparisons of these techniques predated identification of the PPOX gene. We assessed these techniques in a large group of patients characterized for VP at the DNA level. METHODS: We evaluated all patients for whom the genotype and a plasma scan or fecal porphyrin result were available. Mutations were detected by restriction digest analysis. Plasma fluorescence scanning was conducted according to published methods. Fecal porphyrins were identified and quantified by thin-layer chromatography. RESULTS: Plasma fluorescence scanning was assessed in 679 patients (205 with VP who were carriers of a PPOX mutation, either with disease symptoms or asymptomatic) and fecal analysis in 473 (190 with VP). Sensitivity and specificity of both tests were higher in adults than in children and higher for adults with disease symptoms than for asymptomatic carriers. In a direct comparison in 168 adults (73 with VP), plasma scanning was significantly more sensitive than fecal porphyrin analysis [sensitivity, 0.96 (95% confidence interval, 0.89-0.99) vs 0.77 (0.66-0.85)]. Fecal coproporphyrin [area under the curve, 0.87 (0.83-0.90)] was a better predictor of VP than protoporphyrin [0.80 (0.76-0.84)]. CONCLUSIONS: Plasma scanning is a more sensitive and specific test for VP than fecal porphyrin analysis. Neither test is sensitive in children, and both are less sensitive in asymptomatic carriers than in symptomatic cases. DNA analysis therefore remains the preferred method for the identification of carriers, particularly in children.

Adolescent↗
PubMed2001

Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.

The long-term follow-up of a homozygous variegate porphyria patient revealed severe photosensitivity accompanied by mild sensory neuropathy and IgA nephropathy. A 35T to C transition in exon 2 (I12T) and a 767C to G transversion in exon 7 (P256R) of the protoporphyrinogen oxidase gene were identified from both alleles of the patient's cDNA and genomic DNA samples. Both prokaryotic and eukaryotic expression studies showed that the first mutation in the evolutionary conserved region resulted in a decrease in the protoporphyrinogen oxidase activity in contrast to the polymorphic substitution in exon 7, which affected the function of the enzyme assayed in Escherichia coli but not COS-1 cells.

Base Sequence↗
PubMed1988

Linkage between the variegate porphyria (VP) and the alpha-1-antitrypsin (PI) genes on human chromosome 14.

From family studies close linkage between the gene locus for variegate porphyria (VP) and the alpha-1-antitrypsin (PI) gene became evident. The maximal lod score from male meioses was 4.33 at theta = 0.04 and from both sexes combined 3.56 at theta = 0.12. Three pedigrees were triple informative regarding loci VP, PI, and IGHC (immunoglobulin heavy chain cluster, Gm polymorphism). In two of the respective meioses recombinations were observed, and in both cases the co-segregating VP and PI alleles were separated from the Gm haplotypes. These findings argue in favour of gene order either VP:PI:IGHC or PI:VP:IGHC.

Chromosomes, Human, Pair 14↗
PubMed1998

Molecular analysis reveals a high mutation frequency in the first untranslated exon of the PPOX gene and largely excludes variegate porphyria in a subset of clinically affected Afrikaner families.

A subset of probands from 11 South African families with clinical and/or biochemical features of variegate porphyria (VP), but without the known protoporphyrinogen oxidase (PPOX) gene defects identified previously in the South African population, were subjected to mutation analysis. Disease-related mutation(s) could not be identified after screening virtually the entire PPOX gene by heteroduplex single-strand conformation polymorphism analysis (HEX-SSCP), although three new sequence variants were detected in exon 1 of the gene in three normal controls. The presence of these single base changes at nucleotide positions 22 (C/G), 27 (C/A) and 127 (C/A), in addition to the known exon 1 polymorphisms I-26 and I-150, indicates that this untranslated region of the PPOX gene is particularly mutation-prone. Furthermore, microsatellite markers flanking the PPOX and alpha-1 antitrypsin (PI) gene, on chromosomes 1 and 14, respectively, were used to assess the probability of involvement of these loci in disease presentation. Common alleles transmitted from affected parent to affected child were determined where possible in the mutation-negative index cases. Allelic frequencies of these < > alleles were compared to findings in the normal population, but no predominant disease-associated allele could be identified. Co-segregation of a specific haplotype with the disease phenotype could also not be demonstrated in a large Afrikaner family. It is concluded that further studies are warranted to determine the genetic factor(s) underlying the autosomal dominant pattern of inheritance in molecularly uncharacterized cases showing clinical symptoms of an acute porphyria.

Base Sequence↗
PubMed1994

Effects of heme arginate on cytochrome P450-mediated metabolism of drugs in patients with variegate porphyria and in healthy men.

We investigated the effects of heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without heme, a single infusion of heme arginate (3 mg/kg heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of heme on drug metabolism is P450 isozyme-specific.

Adult↗
PubMed1999

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.

Variegate porphyria (VP) is a low-penetrance, autosomal dominant disorder characterized clinically by skin lesions and acute neurovisceral attacks that occur separately or together. It results from partial deficiency of protoporphyrinogen oxidase encoded by the PPOX gene. VP is relatively common in South Africa, where most patients have inherited the same mutation in the PPOX gene from a common ancestor, but few families from elsewhere have been studied. Here we describe the molecular basis and clinical features of 108 unrelated patients from France and the United Kingdom. Mutations in the PPOX gene were identified by a combination of screening (denaturing gradient gel electrophoresis, heteroduplex analysis, or denaturing high-performance liquid chromatography) and direct automated sequencing of amplified genomic DNA. A total of 60 novel and 6 previously reported mutations (25 missense, 24 frameshift, 10 splice site, and 7 nonsense) were identified in 104 (96%) of these unrelated patients, together with 3 previously unrecognized single-nucleotide polymorphisms. VP is less heterogeneous than other acute porphyrias; 5 mutations were present in 28 (26%) of the families, whereas 47 mutations were restricted to 1 family; only 2 mutations were found in both countries. The pattern of clinical presentation was identical to that reported from South Africa and was not influenced by type of mutation. Our results define the molecular genetics of VP in western Europe, demonstrate its allelic heterogeneity outside South Africa, and show that genotype is not a significant determinant of mode of presentation.

Alleles↗
PubMed1997

Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene.

The porphyrias are disorders that result from the inherited or acquired dysregulation of one of the eight enzymes in the heme biosynthetic pathway. Variegate porphyria (VP) is characterized by deficiencies in protoporphyrinogen oxidase (PPO) and has recently been genetically linked (Z = 6.62) to the PPO gene on chromosome 1q21. In this study, we have identified two sequence variants in the PPO gene in a family with VP. The first is a neutral polymorphism at the -47 position of intron 2; this polymorphism is present in the general population and is unlikely to underlie the VP phenotype. The second is a mutation in the PPO gene in a patient with VP; the mutation consists of an apparently de novo 2-bp insertion in exon 3 of PPO and results in a frameshift and downstream premature termination codon. These data establish that a frameshift mutation in PPO is the underlying mutation in this patient with VP and explain the sporadic occurrence of the phenotype in this family.

Adult↗
PubMed1988

Haem arginate improves hepatic oxidative metabolism in variegate porphyria.

1. The elimination of antipyrine was investigated before and after intravenous administration of haem arginate (3 mg haem kg-1 day-1 on three or four successive days) to six patients with variegate porphyria in remission. 2. Haem arginate decreased the faecal content of protoporphyrin from 557 +/- 91 to 118 +/- 32 (mean +/- s.e. mean) and of coproporphyrin from 144 +/- 19 to 19 +/- 3 nmol g-1 dry weight. 3. Before haem treatment antipyrine elimination half-life was long (30.5 +/- 5.6 h), but the treatment decreased it to 6.3 +/- 0.8 h. Antipyrine clearance increased from 0.25 +/- 0.05 to 1.03 +/- 0.11 ml min-1 kg-1 (P less than 0.001), being 4.6 times higher after haem arginate infusions. 4. The volume of distribution of antipyrine did not change. 5. The severe impairment of hepatic mixed function oxidase activity even in the symptomless stage of porphyria indicates cautious dosage of drugs primarily eliminated by hepatic oxidative reactions.

Adult↗
PubMed2002

Single-strand conformational polymorphism and denaturing gradient gel electrophoresis in screening for variegate porphyria: identification of two new mutations.

Single-strand conformational polymorphism and denaturing gel electrophoresis were used to screen for mutations in the protoporphyrinogen oxidase gene (PPOX) of three patients with clinically and biochemically proven variegate porphyria in order to select genomic regions for specific DNA sequence analysis. Two previously undescribed mutations were identified: PPOX1423-1426-delATCT and PPOX2272insG. Denaturing gel electrophoresis was able to discern the point mutation in exon 5 (PPOX2272insG) of the PPOX gene. Once an index individual has been identified, single-strand conformational polymorphism and denaturing gel electrophoresis techniques are useful to identify family members who may be unaffected carriers. Such identification can help potential cases to avoid medications and other triggers that could precipitate acute porphyric attacks.

Adult↗
PubMed1998

The genetic basis of "Scarsdale Gourmet Diet" variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.

The porphyrias are disorders of porphyrin or porphyrin-precursor metabolism that result from inherited or acquired aberrations in the control of the porphyrin-heme biosynthetic pathway. Variegate porphyria (VP), one of the acute hepatic porphyrias, is characterized by a partial reduction in the activity of protoporphyrinogen oxidase (PPO), and recently, mutations in the PPO gene on chromosome 1q22-23 have been described. Our purpose was to identify the underlying genetic lesion in a severely affected patient with VP and to detect the silent mutation carriers in her family. The disease in this patient was precipitated by carbohydrate restriction as outlined in the "Scarsdale Gourmet Diet". Our mutation detection and confirmation strategy included PCR, automated sequencing, and restriction enzyme digestion. We identified a missense mutation in the patient and five family members. The mutation consisted of a previously unreported C-to-T transition in exon 5 of the PPO gene, resulting in the substitution of arginine by cysteine, designated R152C. This arginine residue is evolutionarily highly conserved in humans, mice, bacteria, yeast, and plants, indicating the importance of this residue in PPO. Our study established that a missense mutation in the PPO gene was the underlying mutation in this patient with VP and explained the occurrence of the phenotype in this family.

Amino Acid Sequence↗
PubMed1983

Acute variegate porphyria following a Scarsdale Gourmet Diet.

Symptoms of porphyria developed in a 34-year-old woman following 3 weeks of a low carbohydrate diet. Reversal of a comatose state was obtained following multiple infusions of hematin. The diagnosis of variegate porphyria was made from the pattern of quantitative urine and stool porphyrins and a plasma fluorescence that was maximal at 626 nm. This fluorescence wavelength maxima also was found in the plasma of two family members screened for latent porphyria.

Adult↗
PubMed1998

Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria.

The porphyrias represent a heterogeneous group of disorders of porphyrin or porphyrin-precursor metabolism, resulting from the inherited or acquired dysregulation of one of the eight enzymes in the porphyrin-heme biosynthetic pathway. Variegate porphyria, one of the acute hepatic porphyrias, is characterized by a partial reduction in the activity of the penultimate enzyme in the heme biosynthetic pathway, protoporphyrinogen oxidase (PPO). Recently, VP has been linked to the PPO gene on chromosome 1q22-23, and several disease-causing mutations have been described. In this study, we identified the underlying genetic lesion in two unrelated patients with VP and investigated all available family members by polymerase chain reaction, heteroduplex analysis, automated sequencing, and restriction enzyme digestion. Mutation analyses in both families revealed a G-to-A transition in exon 6 of the PPO gene resulting in the substitution of arginine by histidine at position 168 of the protein (R168H). This arginine residue is evolutionarily conserved in human, mouse, and Bacillus subtilis, indicating the importance of this residue in PPO function. Our study establishes a recurrent missense mutation as the underlying genetic defect in two unrelated patients with VP and explains the occurrence of the phenotype in their families.

Adult↗
PubMed2004

Variegate porphyria presenting with acute autonomic dysfunction, intussusception and renal infarction.

A 48-year-old man presented with abdominal pain, constipation and irritability one month after starting phenytoin treatment for a generalized seizure. He was hypertensive, tachycardic (BP 174/98, heart rate (HR) 100 bpm supine) and hypovolaemic. Abdominal CT demonstrated transient jejunal intussusception and infarction of the left kidney. Urinary porphobilinogen levels were increased and genetic analysis confirmed the diagnosis of variegate porphyria. Because of ongoing postural hypotension, the patient underwent further autonomic investigations. Levels of blood pressure (MBP), HR and muscle sympathetic activity (MSNA) were increased during the acute attack compared to recovery (131 versus 105 mmHg, 100 versus 60 bpm, 88 versus 26 bursts min(-1)). HR and MSNA did not increase during phase II Valsalva, whereas stroke volume (SV) decays were exaggerated (deltaMBP-56 versus 0-31 mmHg and SV 25% versus 40% baseline). Baroreflex failure causing increased sympathetic activity, decreased sympathetic and parasympathetic rapid responses, loss of splanchnic capacitance and renal salt wasting were the likely mechanisms for postural hypotension. Increased sympathetic activity may also have caused intussusception and focal renal vasoconstriction, both of which may be underdiagnosed causes of abdominal pain in acute porphyria.

Acute Disease↗
PubMed1987

Homozygous variegate porphyria. A severe skin disease of infancy.

A boy exhibited severe bullous skin disease a few days after birth, followed by increased fragility of the exposed skin in spring and summer. Examination at 2 1/2 years of age led to characteristic biochemical findings: increased excretion of fecal porphyrins (coproporphyrin 121 to 131 and protoporphyrin 467 to 576 nmol/g dry weight), and increased erythrocyte protoporphyrin concentration (3643 to 4840 nmol/l). Lymphocyte protoporphyrinogen oxidase activity was very low in the patient (0.4 nmol/mg protein/h) and half-normal (2.7 and 2.3 nmol/mg protein/h) in the parents, suggesting that the patient had homozygous variegate porphyria. Severe skin symptoms and a high concentration of red cell protoporphyrin concentration in an infant should prompt suspicion of homozygous acute hepatic porphyria.

Acute Disease↗