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PubMed1980

Erythrocyte porphyrinogen carboxy-lyase activity in porphyria cutanea tarda and certain other human porphyrias.

Red cell porphyrinogen carboxy-lyase activity was measured using uroporphyrinogen III as substrate in 18 normal persons, 7 male patients with porphyria cutanea tarda, 3 female patients with erythropoietic protoporphyria and 2 female patients with variegate porphyria. The mean values obtained in normal subjects were 0.151 nmol of uroporphyrinogen disappeared in 30 min per mg of protein, and 0.038 nmol of coproporphyrinogen formed in 30 min per mg of protein. We have not been able to detect significant differences between males and females. In porphyria cutanea tarda the enzyme activity was the same as in normal subjects considering either substrate disappearance or end product formation. The differences were not significant at the p less than 0.05 level. Patients with variegata porphyria also exhibited normal erythrocyte porphyrinogen carboxy-lyase activity. The enzyme activity of erythrocytes from patients with erythropoietic protoporphyria was higher than in normals; mean values for specific activities being 0.204 nmol of uroporphyrinogen disappeared, and 0.071 nmol of coproporphyrinogen formed. The significance of the results with respect to the chemical picture of different porphyrias is discussed.

Carboxy-Lyases↗
PubMed1976

Porphyria variegata and porphyria cutanea tarda in siblings: chemical and genetic aspects (addendum).

A porphyria kindred in which the index case has porphyria variegata had also been shown to include a case of porphyria cutanea tarda, typical both from chemical and clinical features. The possibility that this was purely acquired rather than genetic seemed unlikely, but could not be wholly excluded. Recently, a niece of both of these cases, although asymptomatic, has been found to conform chemically with porphyria cutanea tarda, including the excretion of the isocoproporphyrin series, and thus represents the second case of this form of porphyria in this family. This strengthens the concept of genetic heterogeneity in this kindred and supports the suggestion of a double heterozygosity, as proposed in the primary paper [Watson, C.J. et al. (1975) Proc. Nat. Acad. Sci. USA 72, 5126-5129].

Heterozygote↗
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

The role of iron in experimental porphyria and porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) and experimental porphyria are characterized by a decreased activity of the enzyme uroporphyrinogen decarboxylase, and accumulation of uroporphyrins and heptacarboxylporphyrins in the liver. Iron (Fe) plays an important role in PCT and experimental porphyria. Biochemically and electron microscopically, we examined the relationship between Fe and porphyrins in liver tissue of C57BL/10 mice made porphyric by administration of iron dextran as Imferon (IMF), and in liver biopsies of patients with symptomatic PCT. Accumulation of uroporphyrins and heptacarboxylporphyrins, and an increased amount of Fe were observed in livers of mice treated with IMF and in liver biopsies of patients with PCT. In mice treated with IMF, the activity of uroporphyrinogen decarboxylase was decreased. Both in livers of mice treated with IMF and in livers of patients with PCT, needle-like structures, representing uroporphyrin crystals, were observed by electron microscopy. Uroporphyrin crystals and Fe (as ferritin) were observed in the same hepatocyte. Moreover, there was a striking morphological correlation between uroporphyrin crystals and ferritin-Fe, suggesting a role for (ferritin-)Fe in the pathogenesis of porphyria.

Animals↗
PubMed1980

[Acute intermittent porphyria versus porphyria variegata: a diagnostic uncertainty (author's transl)].

The authors study a case of acute porphyria in a young woman who was taking oral contraceptives and who began having abdominal pain and bilateral radial paralysis with neuropsychic disorders. The quantitative and chromatographic analyses of urine, feces, and liver porphyrins revealed a pattern of excretion compatible but not definite of porphyria variegata, making this an example of porphyria of difficult noslogic placement. The problems of classification, the action of the contraceptive drugs as probable triggering agents (of the clinical picture) by means of their action on the ALA-synthetase, the rare form of neuropathy, and the rarity of these types of porphyrias in our country are analyzed and discussed. The patient did not present the endocrine-metabolic disorders that are commonly evidenced in these cases.

Acute Disease↗
PubMed1981

Hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda?

Uroporphyrinogen decarboxylase levels were measured in haemolysed whole blood or fibroblasts from 3 unrelated patients with hepatoerythropoietic porphyria (HEP) and in 4 unrelated patients with familial porphyria cutanea tarda, a condition in which the enzyme is defective. In HEP patients enzyme activities were 7% of normal in erythrocytes and 8% of normal in cultured skin fibroblasts. All the features of HEP, including the characteristic accumulation of protoporphyrin in erythrocytes, are secondary to this enzyme defect. The father of 1 HEP patient was heterozygous for the same enzyme defect. He also had uroporphyrinuria and was therefore indistinguishable from patients with subclinical familial porphyria cutanea tarda. It is suggested that patients with HEP are homozygous for the gene that causes porphyria cutanea tarda.

Child↗
PubMed1978

Tryptophan pyrrolase, the regulatory free haem and hepatic porphyrias. Early depletion of haem by clinical and experimental exacerbators of porphyria.

1. The importance of the early depletion of liver haem in the production of porphyria is discussed and further supporting evidence is presented from experiments with tryptophan pyrrolase, under conditions of exacerbation of experimental porphyria by therapeutic and other agents. 2. In addition to the early depletion of pyrrolase haem by porphyrogens, a further depletion is produced when rats are given a porphyrogen plus an analogue or one of 19 drugs known to exacerbate the human disease. 3. Non-exacerbators of human porphyrias do not cause a further early depletion of pyrrolase haem and it is suggested that this system may be used as a screening test for possible exacerbation of the disease by new and existing drugs. 4. A similar further early depletion of haem is produced by combined administration of lead acetate plus phenobarbitone, thus suggesting that the depletion is a more general phenomenon in experimental porphyria. 5. The relationship between tryptophan pyrrolase and the regulatory free haem is discussed. It is suggested that pyrrolase may play an important role in the regulation of haem biosynthesis.

Animals↗
PubMed1975

Differentiation of porphyria cutanea tarda symptomatica from other types of porphyria by measurement of isocoproporphyrin in faeces.

The faecal porphyrin patterns of 24 patients with porphyria cutanea tarda symptomatica (PCTS), eight patients with variegate porphyria, three patients with other types of porphyria, and 20 non-porphyrics subjects have been compared using a two-demensional thin layer chromatographic technique that separates porphyrins of the isocoproporphyrin series from other faecal porphyrins. The 'isocoproporphyrin': coproporphyrin ratio ranged from 0-1 to 5-6 for patients with PCTS, whereas in other types of porphyria and non-porphyric subjects it was 0-05 or less.

Chromatography, Thin Layer↗
PubMed1976

Hexachlorobenzene porphyria in rats as a model for human chronic hepatic porphyrias.

1. Hexachlorobenzene porphyria in the rat provides a suitable experimental model of the stages of development of human chronic hepatic porphyria. Just as in chronic hepatic porphyria in man, the development of experimental HCB porphyria in the rat can be divided into several stages. 2. The findings in this study indicate that porphyrins increase in the urine, liver, kidney, and spleen, and to a lesser degree in the serum, with uroporphyrin and heptacarboxylic porphyrin predominating. 3. In contrast to the distribution of porphyrin accumulation in the various organs, clear evidence of a uroporphyrinogen decarboxylase defect was found only in the liver. Formation of uroporphyrin and heptacarboxylic porphyrin by homogenized HCB kidney tissue did not deviate significantly from that by control kidney. The defect could not be unequivocally evaluated in the spleen because the spleen, like the red cells, normally forms considerable amounts of uroporphyrin from porphobilinogen, which were increased only a few times over in synthesis by the HCB spleen. 4. Isomer studies provide no evidence for an additional uroporphyrinogen cosynthase defect.

Aminolevulinic Acid↗
PubMed2000

Porphyrins, porphyrin metabolism and porphyrias. II. Diagnosis and monitoring in the acute porphyrias.

The acute porphyrias constitute a group of metabolic disorders engaging enzymes in the haem synthetic chain and generally following dominant inheritance patterns. Some gene carriers are vulnerable to a range of exogenous and endogenous factors, which may trigger neuropsychiatric symptoms. Early diagnosis is of prime importance since it makes way for counselling with the aim to block the development of acute, as well as late, disease. The medical and psycho-social consequences of a porphyria diagnosis are considerable and the freedom for maldiagnosis correspondingly small. The strain imposed upon the diagnostic process makes management in specialized laboratories necessary. Inadvertent handling of the diagnostic procedures in laboratories lacking in knowledge, experience and technical competence is repeatedly the reason for harmful underdiagnosis and overdiagnosis. Gene diagnosis of the carrier condition, principally within reach in all types of acute porphyria, is of incomparable versatility and accuracy. However, despite recent great achievements in the molecular biology of porphyric disease, genomic procedures cannot replace biochemical methods in monitoring the activity and progress of the disease, or the effects of therapy. The classical methods are also useful when it comes to screening for the associated disease states. In these tasks, professional handling of the methods and skillful interpretation of the results are of paramount importance. Knowledge of the limitations and pitfalls of the procedures is a guard against maldiagnosis, which may be fatal. In the article the main diagnostic challenges are discussed; the strategy for early detection of the gene carrier state, the recognition and surveillance of the acute porphyric crisis, the evaluation of subacute/subchronic symptoms, the differential diagnoses of the cutaneous porphyrias and the monitoring of late complications.

Acute Disease↗
PubMed2000

Mutations in familial porphyria cutanea tarda: two novel and two previously described for hepatoerythropoietic porphyria.

Uroporphyrinogen decarboxylase (URO-D) deficiency is responsible for two forms of genetic cutaneous porphyria: familial porphyria cutanea tarda (f-PCT) and hepatoerythropoietic porphyria (HEP). The f-PCT transmitted as an autosomal dominant trait, is characterized by photosensitive cutaneous lesions frequently associated to hepatic dysfunction and is precipitated by various ecogenic factors. The HEP, transmitted as a recessive trait, is more severe than f-PCT and would be considered as the homozygous form of f-PCT. For the mutational analysis of f-PCT patients, the entire URO-D gene was amplified and each exon, intron-exon boundaries and the promoter region were cycle sequenced. Five mutations were found in 6 unrelated families studied, of these, two were new: a nonsense mutation in exon 6 (W159X) and a splice defect in intron 9 (IVS9(-1)G-->C). The other two missense mutations, P62L and A80G, had been previously reported in the homozygous state in HEP families. The g10insA, reported in our laboratory, was again identified in other two unrelated families. In addition 3 novel URO-D polymorphisms in non-coding regions were found. The reverse transcription-PCR and sequencing of the splice mutation carrier's RNA did not reveal the presence of an abnormal mRNA, suggesting that no stable transcript from the mutated allele is synthesized. These results increase to 39 the number of mutations identified in the URO-D gene; 4 of them causing both HEP and f-PCT.

Adult↗
PubMed1996

Hepatoerythropoietic porphyria: relationship with familial porphyria cutanea tarda.

Hepatoerythropoietic porphyria is characterized by an early beginning of severe photosensitivity, with an increase in urinary uroporphyrin excretion and other porphyrins, high isocoproporphyrin fecal levels and an accumulation of protoporphyrin in erythrocytes. It is caused by a dramatic decrease in the activity of the uroporphyrinogen decarboxylase. We report a clinical, biochemical and enzymatic study in a family, where a 2-year-old girl suffers from a hepatoerythropoietic porphyria, and the patient's maternal uncle from a porphyria cutanea tarda. We discuss the relationship between these diseases and their known mutations.

Child, Preschool↗
PubMed1992

[Enzymatic and molecular studies in a case of hepato-erythropoietic porphyria. Homozygote form of type familial cutaneous porphyria].

BACKGROUND: Porphyrias are either hepatic or erythroid, depending on the principal site of the specific enzymatic defect. Homozygous uroporphyrinogen decarboxylase deficiency, known as hepato-erythropoietic porphyria (HEP), can involve several mutations. CASE REPORT: A young man, aged 20 years, had gradually developed photosensitivity since the age of 1 year, leading to hypertrichosis and sclerodermoid changes in sun-exposed areas of skin. He displayed high urinary uroporphyrin and 7-carboxylic porphyrins, and elevated fecal and red blood cell iso-coproporphyrin and coproporphyrin. Erythrocyte uroporphyrinogen decarboxylase activity of the patient was reduced to 18% of normal control values, while those of his grandmother and his half-brother were 62-65% of normal. MOLECULAR BIOLOGY: Amplification of the genomic DNA by PCR and hybridization with allele-specific oligonucleotides (ASOs) demonstrated the presence of a Gly 281-->Glu mutation in the patient and in his grandmother and half-brother. CONCLUSION: Enzymatic studies and details of the familial lineage are important for precisely classifying this type of porphyria. Molecular biology studies are necessary before considering any future gene therapy.

Adult↗
PubMed1995

[Porphyria cutanea tarda and hepatoerythropoietic porphyria].

Porphyria cutanea tarda (PCT) is induced by an enzyme deficiency of hepatic uroporphyrinogen decarboxylase activity. As the result of this enzyme deficiency, uroporphyrin and coproporphyrin accumulate to the skin and other organs. These porphyrins are excreted into urine because of their easy solubility in water. Exposure to the sunlight of the porphyrin-rich skin induces cutaneous changes. Porphyria cutanea tarda develops mainly in middle-aged males, sometimes in females. Ethylalcohol, estrogenic hormones, and hemodialysis are reported as provocative factors. Hyperpigmentation on exposed areas, skin fragility, vesicles and erosions are common in PCT. Histopathologically, subepidermal bulla is a characteristic finding in PCT. PAS positive materials are also prominent around the small blood vessels in the dermis and dermo-epidermal junctions. Hepatoerythropoietic porphyria (HEP) is usually manifest in early childhood with dark urine and reveals severe cutaneous photosensitivity. This disease is a homozygous form of type II PCT.

Estrogens↗
PubMed1976

Studies in porphyria. V. Drug oxidation rates in hereditary hepatic porphyria.

The mean plasma half-life (T1/2) of antipyrine was prolonged (21.69 +/- 1.92 hr) in a group of 10 patients with hereditary hepatic porphyria, 8 of whom had acute intermittent porphyria (AIP) confirmed by decreased erythrocyte uroporphyrinogen-1-synthetase (URO-S) activities and 2 of whom had mixed hepatic porphyria, in comparison to the mean of 20 normal control subjects (12.65 +/- 0.86 hr, p less than 0.01). Antipyrine T1/2 was especially prolonged in patients with a history of more severe symptoms, but there was no correlation with the degree of elevation in urinary excretion of the porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). In 7 completely latent carriers of the AIP gene defect who had normal urinary ALA and PBG levels, the elimination rates of antipyrine from plasma were entirely normal. Phenylbutazone T1/2s were normal in 10 porphyric patients tested. These results demonstrate that the cytochrome P-450-dependent enzyme system for oxidizing antipyrine, but not that for phenylbutazone, is impaired in some AIP individuals in whom the gene defect for the disorder is clinically expressed and that this impairment may be related to the severity of the disease. The partial decrease in URO-S activity characteristic of AIP does not result in a profound or generalized decrease in hepatic cytochrome P-450 function, however, even when there is sufficient derangement in the hepatic heme biosynthetic pathway to lead to excessive excretion of chemical intermediates in the pathway.

Adult↗
PubMed1985

Hereditary uroporphyrinogen-decarboxylase deficiency predisposing porphyria cutanea tarda (chronic hepatic porphyria) in females after oral contraceptive medication.

Porphyria cutanea tarda (PCT) was diagnosed in 27 women aged 23-48 years (mean, 35 years) who had been under oral-hormonal-contraceptive medication for 1-18 years, in 3 women under substitutional estrogen treatment in the menopause, and in 2 men aged 65 and 76 years after estrogen treatment of prostatic carcinoma. In all patients, total urinary porphyrin excretion was elevated, with an average uro- and heptacarboxyporphyrin predominance of 88%, thus proving PCT. Of the patients, 84% showed a significant decrease of erythrocyte uroporphyrinogen-decarboxylase (UD; EC 4.1.1.37) activity to approximately 50% of control levels suggesting a hereditary predisposition for the development of a chronic hepatic porphyria. Estrogens and alcohol are capable of reducing hepatic UD activity. Women with hereditary red cell UD deficiency may be regarded as predisposed to PCT when under estrogen intake, especially in combination with the potentiating influence of alcohol and chronic liver disease. Normal erythrocyte UD values in patients with additive alcohol consumption may implicate a stronger inhibitory effect for alcohol on UD, suggesting a merely toxic form of chronic hepatic porphyria.

Adult↗
PubMed1984

Hepatoerythropoietic porphyria: a variant of childhood-onset porphyria cutanea tarda. Porphyrin profiles and enzymatic studies of two cases in a family.

Hepatoerythropoietic porphyria is a rare variant of porphyria cutanea tarda, manifested clinically as photosensitivity starting in early childhood. Biochemically, there are elevated levels of protoporphyrin in erythrocytes and acetate-substituted porphyrins in the plasma, urine, and feces. Uroporphyrinogen decarboxylase activities in these patients are markedly suppressed. Thus far, only nine patients have been reported. We hereby describe the clinical manifestations, histologic changes, porphyrin profiles, and erythrocyte uroporphyrinogen decarboxylase determinations of two additional patients, 9-year-old and 7-year-old siblings, that are consistent with those of nine previously reported patients with hepatoerythropoietic porphyria.

Child↗
PubMed2006

Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.

Congenital erythropoietic porphyria (CEP), an autosomal recessive disorder, is due to mutations of uroporphyrinogen III synthase (UROS). Deficiency of UROS results in excess uroporphyrin I, which causes photosensitization. We evaluated a 3-year-old boy with CEP. A hypochromic, microcytic anemia was present from birth, and platelet counts averaged 70 x 10(9)/L (70,000/microL). Erythrocyte UROS activity was 21% of controls. Red cell morphology and globin chain labeling studies were compatible with beta-thalassemia. Hb electrophoresis revealed 36.3% A, 2.4% A(2), 59.5% F, and 1.8% of an unidentified peak. No UROS or alpha- and beta-globin mutations were found in the child or the parents. The molecular basis of the phenotype proved to be a mutation of GATA1, an X-linked transcription factor common to globin genes and heme biosynthetic enzymes in erythrocytes. A mutation at codon 216 in the child and on one allele of his mother changed arginine to tryptophan (R216W). This is the first report of a human porphyria due to a mutation in a trans-acting factor and the first association of CEP with thalassemia and thrombocytopenia. The Hb F level of 59.5% suggests a role for GATA-1 in globin switching. A bone marrow allograft corrected both the porphyria and the thalassemia.

Amino Acid Sequence↗