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PubMed2003

Genetic analysis of variegate porphyria (VP) in Italy: identification of six novel mutations in the protoporphyrinogen oxidase (PPOX) gene.

Variegate Porphyria (VP) is one of the acute hepatic porphyrias, and is clinically characterised by skin lesions and acute neuropsychiatric/visceral attacks that occur separately or together. The disorder is caused by a partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway, and a number of mutations have been described for the corresponding gene (PPOX). Here we report a genetic analysis of VP in Italy, and the identification of six novel and three previously characterised mutations from nine affected individuals and families. Among those newly identified, two mutations were small deletions (c.418_419delAA; c.759delA), leading to the formation of premature stop codons, two were splicing defects (IVS10+2T>G; IVS12+1G>C), one was a nonsense (c.384G>A=p.W128X) and one a missense mutation (c.848T>A=I283N). This is the first study of the molecular genetics of Variegate Porphyria in patients of Italian origin, and the finding of six novel mutations out of nine identified confirms the genetic heterogeneity observed for this disorder.

Adult↗
PubMed1997

Large phlebotomy in variegate porphyria.

There are no reports on effects of large blood losses in acute hepatic porphyria. In the present study we report the experiences of repeated large therapeutic phlebotomies in a patients with porphyria cutanea tarda coexisting with variegate porphyria. Neither a series of 12 phlebotomies, 300 mL each, resulting in a 17% decrease in blood haemoglobin, nor a single 400 mL phlebotomy activated the acute porphyric condition. It is concluded that the increased bone marrow metabolic throughput resulting from blood loss, in acute types of porphyria does not overload the normoblast or leukocyte precursor haem synthetic pathways in a way which will increase porphyrin precursor excretion or trigger acute porphyric symptoms.

Female↗
PubMed1987

Defective hepatic anion transport in variegate porphyria.

A 29-yr-old man with neurological symptoms that included tremor, dysarthria, and loss of consciousness was diagnosed as having variegate porphyria, because of increased urinary excretion of delta-aminolevulinic acid, porphobilinogen, uroporphyrin, and coproporphyrin, and increased fecal uro-, copro-, and protoporphyrins. He showed marked retention of indocyanine green (R15 min: 53%-78%) and bromosulfophthalein (R45 min: 24%-10%) as well. The kinetic analysis revealed that both hepatic uptake and hepatic excretion were decreased for both dyes. Results of other liver function tests were unremarkable except for intermittent hyperbilirubinemia (0.7-3.3 mg/100 ml), of which the ratio of conjugated and unconjugated fraction was between 0.7 and 1.2. Binding of serum protein and indocyanine green or bromosulfophthalein was normal. An angiographic and scintigraphic study of the liver was normal. A minimal deposition of hemosiderin pigment was found in liver biopsy specimen without other abnormalities. Deposition of porphyrin was not present in the liver. Plasma exchange and erythrocytapheresis did not show any beneficial effects on the clinical and laboratory abnormalities of the patient. A possible relationship between variegate porphyria and defective hepatic anion transport is discussed.

Adult↗
PubMed1995

Variegate porphyria: diagnostic value of fluorometric scanning of plasma porphyrins.

Variegate porphyria (VP) is a dominantly inherited acute hepatic porphyria characterized by a 50% decrease in activity of protoporphyrinogen oxidase (PO) which catalyses the last step of heme biosynthesis. In VP families, most of the gene carriers are asymptomatic but at risk of developing acute attacks if subjected to precipitating factors. Recognition of the carrier status is the first step of an efficient preventive care. This could be achieved by measurement of PO activity which is a sensitive and specific but tedious method. A specific plasma fluorometric emission at 626 nm has been shown in VP patients. Here we show that this simple and inexpensive method is specific but poorly sensitive, especially in detection of asymptomatic carriers. We conclude that this procedure should not replace PO activity measurement in VP family studies.

Adolescent↗
PubMed1998

Molecular basis of variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.

Variegate porphyria (VP) is an autosomal dominant disorder characterised by a partial defect in the activity of protoporphyrinogen oxidase (PPO), and has recently been genetically linked to the PPO gene on chromosome 1q22-23 (Z=6.62). In this study, we identified a mutation in the PPO gene in a patient with VP and two unaffected family members. The mutation consisted of a previously unreported T to C transition in exon 13 of the PPO gene, resulting in the substitution of a polar serine by a non-polar proline (S450P). This serine residue is evolutionarily highly conserved in man, mouse, and Bacillus subtilis, attesting to the importance of this residue. Interestingly, the gene for Gardner's syndrome (FAP) also segregates in this family, independently of the VP mutation. Gardner's syndrome or familial adenomatous polyposis (FAP) is also an autosomal dominantly inherited genodermatosis, and typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. The specific gene on chromosome 5 that is the site of the mutation in this disorder is known as APC (adenomatous polyposis coli), and the gene has been genetically linked to the region of 5q22.

Adenomatous Polyposis Coli↗
PubMed2001

Non-alcoholic steatohepatitis induced by carbamazepine and variegate porphyria.

A 42-year-old woman presented with acute bullous skin lesions and angio-oedema that had developed 3 months after initiation of treatment with carbamazepine for epilepsy. Chromatographic analysis of urinary porphyrins was compatible with variegate porphyria. This was manifested initially by neurological symptoms that were mistaken for epilepsy and later by cutaneous symptoms also. Histological findings excluded hepatic porphyria, but revealed severe fatty changes thought to be caused by idiosyncratic metabolism of carbamazepine. While the porphyrinogenicity of carbamazepine is well known, the presence of variegate porphyria has not been reported. The toxic hepatic effects of the drug on hepatic cytochrome P-450, which is involved in haem metabolism, could have aggravated the pre-existent porphyria, provoking the onset of skin lesions.

Adult↗
PubMed1983

Variegate porphyria and heavy metal poisoning from ingestion of "moonshine".

A patient with cavitary tuberculosis, hepatic cirrhosis, bullous skin lesions over sun-exposed surfaces, disorientation, and a chronic, as well as recent, history of illicit alcohol consumption was found to have acute variegate porphyria by characteristic fecal and urinary porphyrin studies. Elevated levels of lead and arsenic were found in serum and urine without evidence of heavy metal storage in hair and liver. We suspect that the variegate porphyria was precipitated by the ingestion of heavy metals contained in illicit alcohol. In a patient with disorientation, bullous skin lesions, and a history of illicit alcohol ingestion, one must consider heavy metal intoxication and secondary porphyrin abnormalities.

Aged↗
PubMed1981

An acute attack of variegate porphyria complicated by severe autonomic neuropathy.

A patient with familial variegate porphyria is described. She was admitted in an acute attack and developed severe dysautonomia manifested clinically by postural hypotension, tachycardia and constipation with severe abdominal pain. Whilst formal testing of autonomic function demonstrated the presence of marked abnormalities, peripheral nerve conduction studies were normal.

Acute Disease↗
PubMedDate not supplied

Herbicide-induced experimental variegate porphyria in mice: tissue porphyrinogen accumulation and response to porphyrogenic drugs.

Administration of oxadiazon or oxyfluorfen (1000 ppm in the diet) to male BALB/c mice for 9 days resulted in experimental porphyria, resembling the acute phase of human variegate porphyria. Urinary concentrations of 5-aminolevulinic acid and porphobilinogen reached 1500 and 3000 mumol/L, respectively. Both herbicides caused a decrease of protoporphyrinogen oxidase activity in liver and kidney. Brain protoporphyrinogen oxidase activity was not altered. Liver and kidney porphyrin content increased to 11 and 17 nmol/g, respectively (control mice, 2 nmol/g). Over 50% of liver and kidney porphyrins were in the reduced (porphyrinogen) form. Bile of oxadiazon-treated mice contained 700 nmol/mL of protoporphyrinogen (control mice, 15 nmol/mL). Porphyrin content of the trigeminal nerve increased from 1 nmol/g in control animals to 11 nmol/g in oxadiazon-treated animals, suggesting a possible contribution of peripheral nerve porphyrins to porphyric neuropathy. Mice treated with 125 ppm of oxadiazon in the diet for 9 days excreted moderately elevated levels of porphobilinogen in urine (control mice, less than 50 mumol/L; treated mice, 330 mumol/L). Administration of phenobarbital or phenytoin (single injections on days 7, 8, and 9) increased the urinary porphobilinogen concentration to 3500 mumol/L. This response to porphyrogenic drugs resembles the response observed in human acute porphyrias.

Animals↗
PubMedDate not supplied

Variegate porphyria with unusual neurologic manifestations.

A 62-year-old man with variegate porphyria is reported. This is the first case to be described in Greece. Apart from the common features of the disease this patient exhibited sensory loss of the syringomyelic type. Though variegate prophyria with neurologic manifestations is not uncommon syringomyelic type of sensory loss is most unusual.

Diagnosis, Differential↗
PubMed2003

Administration of oral activated charcoal in variegate porphyria results in a paradoxical clinical and biochemical deterioration.

BACKGROUND: Porphyrinogens are the obligate intracellular precursors of haem. These compounds are, however, unstable and are easily oxidized to the corresponding porphyrins, which are the form in which they are usually measured in the laboratory. A substantial enterohepatic cycling of porphyrins has been shown. Administration of oral activated charcoal, by interrupting this cycle, may reduce plasma and urine porphyrin levels in patients with some forms of porphyria. The effect of charcoal in subjects with variegate porphyria (VP) has not been reported. OBJECTIVES: To determine the clinical and biochemical effects of the administration of oral activated charcoal in patients with VP. METHODS: Oral activated charcoal was administered to eight subjects with VP. Clinical activity was assessed by skin lesion counts fortnightly for 6 weeks, 6 weeks after cessation of therapy, and during a subsequent 6-week control period during which no charcoal was taken. Urine and plasma porphyrins and urine precursors were measured by standard techniques. RESULTS: Treatment resulted in a significant increase in skin disease, urine and plasma porphyrins. CONCLUSIONS: Oral charcoal administration results in a paradoxical aggravation of VP, suggesting a complex and as yet undefined interaction of hepatic porphyrin metabolism and bowel porphyrin reabsorption. Oral sorbents should not be prescribed to subjects with VP.

Administration, Oral↗
PubMed1990

Skin changes in variegate porphyria. Clinical, histopathological, and ultrastructural study.

The skin of 20 patients with variegate porphyria (VP) was studied using light, fluorescent, and electron microscopy. Twelve patients had skin symptoms and markedly increased fecal protoporphyrin excretion. Their sun-exposed skin was characterized by homogeneous PAS-positive thickening and IgG deposition in the vessel walls. The basic ultrastructural change was thickening of the vascular walls caused by reduplication of the basal lamina and perivascular deposition of amorphous material. Qualitatively similar but less prominent histopathological changes occurred in sun-protected skin in some of the patients. Six patients had no skin symptoms but an increased porphyrin excretion. The light microscopical changes were comparable to those in the patients with skin symptoms, but the ultrastructural changes were less severe. No abnormal histopathological changes occurred in two symptomless patients who had low lymphocyte protoporphyrinogen oxidase activity but normal fecal porphyrin excretion. These results show that the primary site of skin damage in VP is the vessel wall, and that histopathological changes of the skin also occur in porphyric patients who have never had skin symptoms. Factors determining the occurrence of skin symptoms in VP are discussed.

Adult↗
PubMed1982

A tightly bound protein-porphyrin complex isolated from the plasma of a patient with variegate porphyria.

Free acid porphyrins were isolated from plasma of a patient with variegate porphyria. Part of the total porphyrin content--which included protoporphyrin IX, harderoporphyrin and uroporphyrin in a molar ratio of 1.2:1:0.5 and traces of pentacarboxylic porphyrin--was extractable with ethyl acetate/acetic acid as described previously [1]. Unextractable porphyrins remained in the precipitate formed after mixing the lower liquid layer and precipitate from the extraction procedure (Fig. 1, [1]) with excess ethyl acetate/acetic acid. A portion of this precipitate was hydrolyzed in 8 mol/l HCl; its porphyrins were extracted with N-butanol and analyzed by high pressure liquid chromatography; another portion was chromatographed on Sephadex G-150 with 1 mol/l MgCl2, and the major porphyrin-protein pool was hydrolyzed in 8 mol/l HCl, reacted separately with AgNO3 and Ag2SO4, and subjected to cellulose acetate and polyacrylamide-gel electrophoresis. The results support the hypothesis that a dicarboxylic porphyrin, a major portion of which was unextractable by standard procedures [1] and which appeared to be covalently bound to a protein of approximately 68 000 mol. wt. that moved with human serum albumin during cellulose acetate electrophoresis, is the preponderant porphyrin in this plasma.

Carrier Proteins↗
PubMed1991

Propofol as an i.v. anaesthetic induction agent in variegate porphyria.

The choice of an i.v. anaesthetic induction poses problems for the anaesthetist confronted with a patient with one of the acute porphyrias. We undertook a prospective clinical trial in 13 variegate porphyric subjects using propofol as an anaesthetic induction agent. Urinary porphyrin precursors and porphyrins were measured before operation and 1-5 days after operation. Stool and plasma porphyrin concentrations were measured over the same period. Comparison of these data in the porphyric patients and in 21 control subjects over the trial period revealed no significant change in porphyrin or porphyrin precursor output after operation. Urinary porphyrin precursor concentrations did not exceed the limits established for variegate porphyric patients in remission, and there were no changes in the stool and plasma porphyrin profiles or any symptoms of an acute porphyric attack. We conclude that propofol did not appear to be porphyrinogenic when used for the induction of anaesthesia in 13 patients with variegate porphyria.

Adolescent↗
PubMed2001

Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene.

Homozygous variegate porphyria results from mutations in both alleles of the protoporphyrinogen oxidase (PPOX) gene. Our patient, a 36-year-old woman, has severe cutaneous manifestations. Her clinical and biochemical features are similar to the few other reported cases, including onset before 18 months of age, photosensitivity, absence of acute porphyric attacks, and elevated erythrocyte protoporphyrin. Mutation analysis of the PPOX gene revealed an in-frame 12 bp insert (c. 657-658 ins AAGGCCAGCGCC) encoding lysine-alanine-serine-alanine (KASA), and a G to A transition at the splice donor site of exon 11 (IVS 11-1 G-->A). Neither of these mutations has been reported previously. Our patient's mother has the splice site mutation and has had acute porphyric episodes. A maternal first cousin has the same mutation but no clinical manifestations. The medical and family history of our patient's father is uncertain.

Adult↗
PubMed1996

Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.

Mutation analysis of genomic DNA samples obtained from 17 unrelated South African patients with variegate porphyria (VP) revealed three novel missense mutations in the protoporphyrinogen oxidase (PPOX) gene. A common C to T transition at nucleotide position 452 (R59W) was identified in 15 of the patients analysed, while base changes at positions 336 (H20P) and 779 (R168C) were identified in the remaining two patients. Using protein analysis software we were able to predict that all three mutations have a similar biophysical effect on the protein, being the disturbance of amphiphatic regions within the protein, which might result in misfolding of the protein. Mutation R59W, identified in the majority of South African VP families, was shown to create a Styl restriction site, while mutation R168C would abolish a Dsal restriction site in genomic DNA of affected individuals. As 100% of the index patients analysed were molecularly characterized, the combined use of restriction enzyme and single-strand conformation polymorphism (SSCP) analysis now allows a rapid and accurate diagnosis of VP in South Africa. Mutation R59W was furthermore shown to be in association with one of four potential haplotypes defined by two newly described polymorphisms in exon 1 of the PPOX gene. Our molecular data thus strongly support the founder hypothesis for VP in South Africa.

DNA Mutational Analysis↗
PubMed1975

A case of variegate porphyria in an Indian.

A female patient aged 25 years developed abdominal and neurological symptoms followed by a photosensitive eruption during pregnancy. She was found to have variegate porphyria on investigation. Investigation of the family revealed on member having latent porphyria. To our knowledge, this is the first report of variegate porphytia from India.

Adult↗