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PubMed1989

Uroporphyrinogen decarboxylase and protoporphyrinogen oxidase in dual porphyria.

The urinary and faecal porphyrin excretory profiles of dual porphyria are said to represent the superimposition of those found in porphyria cutanea tarda on those seen in variegate porphyria. To test this hypothesis the enzymes responsible for these conditions, protoporphyrinogen oxidase (variegate porphyria) and uroporphyrinogen decarboxylase (porphyria cutanea tarda) were measured in vitro in haemolysates and lymphoblasts of 10 subjects with dual porphyria in order to clarify the enzymatic defects. Mean protoporphyrinogen oxidase activity in lymphoblasts from subjects with dual porphyria was decreased by 45% from 0.82 +/- 0.10 to 0.45 +/- 0.09 nmol protoporphyrin/mg protein/h (P less than 0.001). Uroporphyrinogen decarboxylase activity was also significantly reduced from 0.12 +/- 0.05 nmol 7-, 6-, 5- and 4-carboxyl porphyrin/mg protein/h in lymphoblasts from normal subjects to 0.08 +/- 0.02 nmol in lymphoblasts of subjects with dual porphyria (P less than 0.01). There was a similar 27% decrease in mean uroporphyrinogen decarboxylase activity of haemolysates from the same dual porphyria group (P less than 0.01). Mean activity of this enzyme in 5 patients with variegate porphyria did not differ significantly from that in normal subjects. These findings may well provide a rational basis for the abnormal porphyrin excretory profiles found in subjects with dual porphyria.

Carboxy-Lyases↗

PubMed1988

Acute hepatic porphyria and hepatocellular carcinoma.

In this study we examined the case histories of 163 living and 82 deceased adult Finnish patients with acute hepatic porphyria. There were 184 patients with acute intermittent porphyria and 61 patients with variegate porphyria. Among the 124 of the 163 living patients, who were traced 1984-1985, no hepatocellular carcinoma was found. Among the 82 deceased patients the cause of death was porphyria in 29 (36%), cardiovascular disease in 23 (29%) and hepatocellular carcinoma in 7 (9%). Of the 7 patients with hepatocellular carcinoma, 6 had acute intermittent porphyria and one had variegate porphyria. In acute hepatic porphyria, as compared with the total population, the calculated risk of hepatocellular carcinoma is increased 61-fold.

Adult↗

PubMed1980

The enzymatic defect in variegate prophyria. Studies with human cultured skin fibroblasts.

Fecal protoporphyrin is increased in patients with variegate porphyria, even during clinical remission, suggesting an enzymatic defect in the terminal portion of the heme biosynthetic pathway. We measured the activities of protoporphyrinogen oxidase, which catalyzes the oxidation of protoporphyrinogen to protoporphyrin, and heme synthase, which catalyzes the chelation of iron to protoporphyrins, in cultured skin fibroblasts from five normal controls and five patients with variegate porphyria. Heme synthase activity was shown to be normal in variegate porphyria cells by direct assay in cell sonicates and indirect assay in intact cells. Protoporphyrinogen oxidase activity, however, was reduced to 43 per cent of normal in sonicates of variegate porphyria cells (0.90 +/- 0.13 vs. 2.12 +/- 0.25 nmol of protoporphyrin per milligram of protein per hour [mean +/- S.E.M.] [P less than 0.005]). We conclude that protoporphyrinogen oxidase activity is deficient in variegate porphyria. Fecal protoporphyrin may increase because an excess amount of protoporphyrinogen is excreted into bile and subsequently auto-oxidized to protoporphyrin.

Adult↗

PubMed1976

Incubation of double labelled coproporphyrinogen with chicken red cell haemolysates, chemical and TLC fractionation of extracts.

Further evidence is presented for the enzymic conversion of protoporphyrinogen to protoporphyrin by observing the loss of 3H counts by 3H and 14C labelled coproporphyrinogen when incubated in chicken red cell haemolysates. Use was made of chemical and TLC fractionation of porphyrin extracts after incubation and a loss of half the 3H was again found. Evidence is presented for the role of harderoporphyrinogen as a natural intermediate in this conversion. The relevance of the findings in the porphyrias, and in particular variegate porphyria, is discussed. It is suggested that the enzymic process involved in the conversion of protoporphyrinogen to protoporphyrin may be deficient in variegate porphyria.

Animals↗

PubMed1992

[Neurological, dermatological and biological manifestations of porphyria variegata. A study of 3 families of Italian origin in Marseilles area].

Three kindreds of Italian descent with variegate porphyria are described. These families are now living in Marseilles and surrounding regions. The first kindred originating from Torre del Greco, near Naples, is living in Arles. This family includes two propositi who experienced an acute attack with visceral and neuropsychiatric manifestations. The family's survey was carried out by measuring protoporphyrogen oxidase (PO) activity in lymphocytes (normal values = 4.8 +/- 1.2). Seven of the 20 subjects tested, beside the two propositi, were found to be asymptomatic carriers (PO < 3.6). The first index patient, a 41-year old man, was first observed at the age of 31 with acute and psychiatric manifestations after rifampicin treatment; the cutaneous symptoms appeared one year later. For the second propositus, a woman presenting with abdominal and psychiatric manifestations, the age of onset was 38 years; the acute attack had no recognizable cause; she had mild skin lesions and initially was incorrectly diagnosed as intermittent acute porphyria; the diagnosis of variegate porphyria was only established at the age of 50 years. The second family, originating from la Spezia and Vernazza, is living in Marseilles. The propositus, a 50-year old man, developed cutaneous symptoms at the age of 30. A diagnosis of porphyria cutanea tarda was initially made. The first and unique acute attack with abdominal and neurological manifestations recurred at the age of 41. The diagnosis of variegate porphyria was established on laboratory data. Physical stress was probably the cause of the acute attack. Beside the propositus, out of 9 subjects tested 6 were asymptomatic carriers.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Pain↗

PubMed1980

General anesthesia in "inducible" porphyrias.

To evaluate the risk of inducing acute symptoms after general anesthesia in patients with "inducible " porphyrias, the authors analyzed retrospectively the effects of 78 exposure to anesthesia in 47 patients, 33 with acute intermittent porphyria and 14 with variegate porphyria. On 62 occasions, 29 involving the use of a barbiturate, anesthesia was induced in 37 patients who had no porphyric symptoms at the time. None of these patients had an acute attack postoperatively. Anesthesia was induced 16 times in 14 patients during acute episodes; 12 of these patients also received precipitating drugs other than anesthetics. Porphyric symptoms worsened in seven in the ten patients who received thiopental and in two of the four who did not. In the latent stages of acute intermittent and variegate porphyria in this patient population, the risk of incurring symptoms after exposure to thiopental and/or other anesthetics was small. During an acute episode thiopental may aggravate porphyric symptoms.

Acute Disease↗

PubMed1987

Red blood cell rhodanese: its possible role in modulating delta-aminolaevulinate synthetase activity in mammals.

The optimum conditions for measuring rhodanese activity in human erythrocytes were established. The mean control values for males (112 nmol SCN/30 min/mg protein) and females (127 nmol SCN/30 min/mg protein) were determined. Rhodanese activity was measured in different porphyric patients. The activity was diminished in porphyria cutanea tarda (PCT), acute intermittent porphyria (AIP), variegate porphyria (VP) and lead intoxication (Pb), remaining normal in erythropoietic protoporphyria (EPP). delta-Aminolaevulinate synthetase (ALA-S) activity was increased in PCT, AIP, VP and Pb showing no changes in EPP. It is suggested that a similar scheme, to that proposed for the control of ALA-S in Rhodopseudomonas spheroides and soybean callus, is also operating in animals.

5-Aminolevulinate Synthetase↗

PubMed2006

Mitochondrial targeting of human protoporphyrinogen oxidase.

Variegate porphyria is an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. This study examined the effect of three South African VP-causing mutations (H20P, R59W, R168C) on mitochondrial targeting. Only H20P did not target, and of eight protoporphyrinogen oxidase-GFP chimeric fusion proteins created, N-terminal residues 1-17 were found to be the minimal protoporphyrinogen oxidase sequence required for efficient mitochondrial targeting. Removal of this N-terminal sequence displayed mitochondrial localization, suggesting internal mitochondrial targeting signals. In addition, six constructs were engineered to assess the effect of charge and helicity on mitochondrial targeting of the protein. Of those engineered, only the PPOX20/H20P-GFP construct abolished mitochondrial targeting, presumably through disruption of the protoporphyrinogen oxidase alpha-helix. Based on our results we propose a mechanism for protoporphyrinogen oxidase targeting to the mitochondrion.

Cell Line, Tumor↗

PubMed1997

Hepatic porphyrias in children.

Clinically overt hepatic porphyria is uncommon in children. The autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), are rarely present before puberty. Identification of asymptomatic children who have inherited these disorders is an important aspect of the management of the disease in their families and requires either enzymatic or DNA methods. Homozygous variants of AIP, VP and HCP usually present in early childhood and have phenotypes of variable severity. Mutational analysis is currently elucidating the relationship between these disorders and their autosomal dominant counterparts. 5-Aminolaevulinate dehydratase deficiency porphyria is a rare, autosomal recessive acute porphyria that may present at any age. Two cutaneous hepatic porphyrias are seen in children. Porphyria cutanea tarda (PCT), although mainly an adult disease, has been reported in young children with the autosomal dominant (type II) form of the disorder. Hepatoerythropoietic porphyria usually develops before the age of 2 years; patients are homo- or heteroallelic for uroporphyrinogen decarboxylase mutations, at least one of which is known to cause type II PCT.

Child↗

PubMed1998

Update on enzyme and molecular defects in porphyria.

Each porphyria results from decreased activity of one of the enzymes of haem biosynthesis. The molecular basis of enzyme deficiencies in acute intermittent porphyria (AIP), variegate porphyria (VP) and congenital erythropoietic porphyria (CEP) is outlined. All three conditions show extensive allelic heterogeneity. In the autosomal dominant disorders, AIP and VP, no genotype/phenotype correlations have been demonstrated, and the explanation for their low clinical penetrance remains uncertain. In AIP and VP, mutational analysis is superior to biochemical methods for screening families for latent porphyria. In the autosomal recessive condition, CEP, there is some genotype/phenotype correlation--one common mutation (C73R) being associated with severe disease in homozygotes. Porphyria cutanea tarda (PCT) is not a simple monogenic disorder. Patients appear to have an inherited susceptibility to inactivation of hepatic uroporphyrinogen decarboxylase (UROD) as part of a response to hepatocyte injury by alcohol, HCV and other agents. Inherited factors that, in combination, may predispose to PCT include mutations in the UROD gene, present in about 20% of patients, and the C282Y mutation in the haemochromatosis (HFE) gene.

Enzymes↗

PubMed1986

Chester porphyria: a clinical study of a new form of acute porphyria.

Acute porphyria afflicts a large kindred in Chester that stems from a marriage in 1896 that has produced 200 descendants; this is the largest porphyric kindred to be identified in the United Kingdom. Six members aged 51 or under died from the condition over the past eight years. The diagnosis of porphyria was overlooked in some as the symptoms may mimic those of other acute illnesses, so that incomplete or incorrect death certificates have been issued. Psychosis, hypertension, and renal complications are particularly common. The porphyric members of the kindred show a previously undescribed hereditary disorder in which the characteristic enzymatic defects of acute intermittent porphyria and variegate porphyria coexist in the same subject. Acute porphyria is poorly understood by hospital and general practitioners, and this has caused anxiety in the kindred. A register of the kindred has been established, and families at risk should be offered biochemical screening, education, and genetic counselling.

Acute Disease↗

PubMed1992

Alcoholic beverages in acute porphyria.

Alcohol consumption habits and the clinical consequences of intake of alcoholic beverages were examined in 254 individuals with a diagnosis of acute intermittent porphyria or variegate porphyria, using a questionnaire. The study failed to demonstrate a connection between the amount of ethanol consumed, or the frequency of ingestion, and the development of symptoms of acute porphyria, other than in extreme consumption patterns. It was concluded that agents in alcoholic beverages other than ethanol play important roles in precipitating the porphyric symptoms. A majority of the individuals were able to identify alcoholic beverages that were less well tolerated and those that were better tolerated. The results suggest that polyphenolic compounds and 3 to 5 carbon chain hydrophobic alcohols may be responsible for the induction of clinical symptoms in acute porphyria by some alcoholic beverages. On the basis of these findings advice is proposed on alcohol counseling in inducible porphyria.

Acute Disease↗

PubMed2004

Porphyrias in Japan: compilation of all cases reported through 2002.

The first case of porphyria on record in Japan was a patient with congenital erythropoietic porphyria (CEP) reported by Sato and Takahashi in 1920. Since then until the end of December 2002, 827 cases of porphyrias have been diagnosed from characteristic clinical and/or laboratory findings (463 males, 358 females, and 6 of unknown sex). Essentially all inherited porphyrias have been found in Japan, with the incidences and clinical symptoms generally being similar to those reported for other countries. The male-female ratio was approximately 1:1 for CEP, whereas it was higher for erythropoietic protoporphyria. In contrast, preponderances of female patients exist with acute hepatic porphyrias, such as acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP), and with undefined acute porphyria. Although porphyria cutanea tarda (PCT) is believed to be increasing recently in women in other countries because of smoking and the use of contraceptives, it is still by far more prominent in males in Japan than in females. The recent increasing contribution of hepatitis C virus infection to PCT in Japan has also been recognized. but there have been no PCT cases in Japan with HFE gene mutations. Familial occurrence and consanguinity were high for CEP, as expected; however, significant consanguinity was also noted in families where CEP, AIP, HCP, VP, or PCT occurred as a single isolated case without a family history of disease. This survey also revealed that as many as 71% of acute hepatic porphyria cases were initially diagnosed as nonporphyria and later revised or corrected to porphyria, indicating the difficulty of diagnosing porphyria in the absence of specific laboratory testing for porphyrins and their precursors in urine, stool, plasma, and erythrocyte samples.

Adolescent↗

PubMed2001

Pseudoporphyria: a clinical and biochemical study of 20 patients.

OBJECTIVE: To describe the clinical and laboratory findings in patients with pseudoporphyria. PATIENTS AND METHODS: This retrospective review identified 261 patients with either porphyrin metabolism abnormalities or pseudoporphyria who were seen at the Mayo Clinic in Rochester, Minn, between 1992 and 1996. All patients with documented porphyria cutanea tarda (PCT), noncutaneous porphyrias, or variegate porphyria were excluded. RESULTS: Twenty patients had active cutaneous lesions resembling PCT with no diagnostic laboratory abnormalities. The major presenting clinical features were blistering in 19 patients (95%), scarring in 14 (70%), photosensitivity in 13 (65%), skin fragility in 13 (65%), and milia in 8 (40%). Histologically, of 17 patients tested, 12 (71%) had classic findings of subepidermal separation with festooning of dermal papillae. None of the 11 patients tested had hepatitis B or C. In all 20 patients, porphyrin profiles were nondiagnostic. Of 16 patients for whom follow-up was available, 11 reported persistent symptoms for a mean of 2.5 years after evaluation. Five patients were free of symptoms 1 week to 6 months after discontinuation of the presumed offending agent. CONCLUSION: Pseudoporphyria mimics the cutaneous symptoms of PCT in the setting of normal or near-normal porphyrin levels in the serum, urine, or stool. Despite efforts to discontinue an offending medication, symptoms may persist indefinitely.

Adult↗

PubMed1999

Porphyria. From Sir Walter Raleigh to molecular biology.

The porphyrias are a group of disorders caused by deficient activity of the enzymes responsible for the biosynthesis of haem. The skin is one of the major organs involved in most of these diseases because the porphyrins which accumulate are phototoxic. The common cutaneous porphyrias are variegate porphyria, porphyria cutanea tarda, congenital erythropoietic porphyria and erythropoietic protoporphyria, each caused by a different enzyme deficiency causing a distinctive pattern of porphyrin accumulation and typical clinical features. The genes encoding these enzymes have all been cloned recently, enabling the genetic defects underlying these disorders to be elucidated. The factors triggering sporadic porphyria cutanea tarda in predisposed individuals are now becoming clear: hepatic iron overload is required to induce the hepatic enzyme defect and many patients are haemochromatosis gene carriers. Hepatitis B, C, and HIV virus infection also contribute to disease expression. In erythropoietic protoporphyria, up to 5% of patients develop liver failure. It is now clear that some of these patients suffer from a different recessively transmitted form of the disease: this finding may make it possible to identify these patients at an earlier stage. Gene therapy holds particular promise as a future therapy and has successfully been used to correct enzyme defects in vitro. Bone marrow transplantation has also been tried in patients with congenital erythropoietic porphyria. The joints are not involved by porphyria. However, some non-steroidal inflammatory drugs prescribed by rheumatologists have phototoxic properties similar to uroporphyrin. These drugs cause a syndrome clinically and histologically indistinguishable from porphyria cutanea tarda which is known as pseudoporphyria.

Humans↗

PubMed2002

Molecular characterization of porphyrias in Italy: a diagnostic flow-chart.

The porphyrias are disorders associated with inherited or acquired enzyme deficiencies in the heme biosynthetic pathway. The differential diagnosis is often difficult since the phenotype is very similar in some forms and the biochemical tests are not commonly available. Here we provide an update on the molecular diagnosis of porphyrias in Italy and a flow-chart to facilitate the identification of mutations in heme biosynthetic genes. The molecular analysis has allowed us to identify the molecular defect underlying the disease in 66 probands with different porphyrias [acute intermittent porphyria (AIP), variegate porphyria (VP), porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP)]. No Italian patients with defects in coproporphyrinogen oxidise (CPOX) gene, responsible for hereditary coproporphyria (HCP), have been detected. The molecular characterization has been extended to 115 relatives with the identification of 55 asymptomatic mutation carriers and 60 normal subjects. We have so far identified 50 different mutations among 4 genes associated with the most common porphyrias showing a high molecular heterogeneity: 22 in the hydroxymethylbilane synthase (HMBS) gene (AIP), 7 in the protoporphyrinogen oxidase (PPOX) gene (VP), 16 in the uroporphyrinogen decarboxylase (UROD) gene (PCT) and 5 in the ferrochelatase (FECH) gene (EPP). Among the 50 molecular defects, 29 seem to be restricted to the Italian population.

DNA↗

PubMed1996

[Acute hepatic porphyria and its neurological syndrome].

Certain of the hepatic porphyrias are classified as belonging to the acute hepatic prophyrias, namely acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and ALA-dehydrase deficiency. The common feature of all acute hepatic porphyrias is the sudden onset of neurological symptoms. The whole syndrome consists of acute abdominal pain crises with autonomic dysfunction, global or focal central nervous system involvement and a predominantly motor polyneuropathy. Mono- or oligosymptomatic manifestations of acute porphyrias occur and are probably underestimated. The laboratory diagnosis of porphyria depends on the measurement of porphyrin precursors in urine, whereas the measurement of porphyrins in urine and feces is essential for evaluation of the porphyria type. Enzyme measurements are used to identify asymptomatic family members whose quantitative excretions of porphyrins are normal. At present the pathogenesis of neurological manifestations of acute porphyrias remains an unsettled question. The major hypotheses are discussed in this paper. The most important precipitating factor in acute hepatic porphyrias is drug ingestion. As many new drugs have not been in use for sufficiently long periods to assess their porphyrogenic activity, it is safer to avoid drugs in patients with porphyria. The most effective treatment of porphyria attacks is the administration of heme. Among the porphyria patients with epileptic seizures requiring antiepileptic medication, treatment with bromides should be taken into consideration.

Abdomen, Acute↗

PubMed1985

Chester porphyria: biochemical studies of a new form of acute porphyria.

A previously unrecognised form of acute porphyria has been identified in a large family in Chester, UK. Patients presented with attacks of neurovisceral dysfunction and none had experienced cutaneous photosensitivity. Biochemically, the excretion pattern of haem precursors varied between individuals; some had a pattern typical of acute intermittent porphyria, others showed that of variegate porphyria, and some had an intermediate pattern. Studies of the enzymes of haem biosynthesis in peripheral blood cells showed a dual enzyme deficiency, with reduced activity of both porphobilinogen deaminase, as seen in acute intermittent porphyria, and protoporphyrinogen oxidase, as seen in variegate porphyria. The genetic basis of this dual form of acute porphyria and its relation to the other acute porphyrias are not clear.

5-Aminolevulinate Synthetase↗