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At least 19 recordsLinked to original sources

PubMed1978

Red-cell uroporphyrinogen decarboxylase activity in porphyria cutanea tarda and in other forms of porphyria.

To test the diagnostic specificity of reduced red-cell uroporphyrinogen decarboxylase activity for porphyria cutanea tarda, we measured enzymic activity in 29 normal subjects and 65 patients with various forms of porphyria. Only patients with porphyria cutanea tarda had subnormal enzymic activity. Patients with acute intermittent porphyria, erythropoietic protoporphyria, variegate porphyria and hereditary coproporphyria had normal or slightly elevated activities. The enzymic activity in normal persons and patients with porphyria cutanea tarda did not differ according to sex. Reduction of iron stores did not alter the enzymic activity in porphyria cutanea tarda. We conclude that reduced red-cell uroporphyrinogen decarboxylase activity is a specific and intrinsic defect in porphyria cutanea tarda; measurement of this enzyme is a reliable diagnostic test for this disease.

Acute Disease↗

PubMed1975

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

A woman aged 54 was studied because of a severe acute porphyric (neurologic) relapse with clinical and chemical findings characteristic of porphyria variegata. During a family survey, her brother, aged 59, was found to have chemical abnormalities typical of porphyria cutanea tarda, without suggestion of neurologic manifestations. He had mild skin changes compatible with either of these forms of porphyria. The sister exhibited the protocoproporphyria of porphyria variegata, together with a large amount of fecal "x" porphyrin fraction, without demonstrable isocoproporphyrins. The brother had a uro-isocopro-type of porphyria in accord with the diagnosis of porphyria cutanea tarda, and quite at variance with the sister's findings. This occurrence of porphyria variegata and porphyria cutanea tarda in siblings is thus far unique. Certain hypotheses are considered in respect to genetic aspects of the differing prophyrias in this sibling pair.

Acute Disease↗

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↗

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↗

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↗

PubMed1975

[Hepato-erythrocytic porphyria. A new type of porphyria].

A case of porphyria with symptomatology beginning in early infancy with peculiar biochemical features is described. There were crops of blisters, an extraordinary hypertrichosis and scarring of the exposed skin. The porphyrin examination showed an abnormal excretion pattern of urinary porphyrins with large amounts of 5-COOH carboxyle porphyrins and the protoporphyrin level of the red cells was raised. There was fluorescence of the erythrocytes and erythroblasts. The porphyrin excretion pattern of the stools was similar to those of the PCT. This case is closely similar to another published by the authors in 1969 and to 2 published by Schneider and Simon. The authors consider that could represent a new type of porphyria.

Child↗

PubMed1975

Studies in porphyria. IV. Expression of the gene defect of acute intermittent porphyria in cultured human skin fibroblasts and amniotic cells: prenatal diagnosis of the porphyric trait.

The gene lesion of the porphyrin-heme synthetic pathway in acute intermittent porphyria (AIP) is reflected in a deficient level of activity of the cytosol enzyme uroporphyrinogen I synthetase (URO-S). A marked URO-S deficiency has been demonstrated in the liver and in circulating erythrocytes of individuals with both active and latent AIP. This enzymic abnormality accounts for the excessive production and excretion into urine of the porphyrin precursors, lamda-aminolevulinic acid (ALA) and porphobilinogen (PBG) in AIP subjects. In this study, utilizing cell culture techniques, a marked URO-S deficiency has also been demonstrated in skin fibroblasts from AIP patients and in cells derived through aminocentesis from an approximately 17-wk old fetus. The prenatal diagnosis of the AIP trait in this fetus was confirmed postnatally by the demonstration in the child of a deficient level of erythrocyte URO-S activity which was comparable to those found in her AIP mother and affected sibling and which was approximately one-half the levels characterizing her normal father and aunt and a second unaffected sibling. The identification of the URO-S deficiency in cultured human fibroblasts from AIP patients was facilitated by a newly developed, sensitive assay for the enzyme activity. In this assay, the ability of such cells to convert ALA to protoporphyrin was quantitated; in the sequence of reactions involved in this transformation, URO-S is limiting so that the gene defect of AIP could be simply and precisely determined by appropriate spectrofluorometry of cell extracts. The technique described has distinct advantages over the direct enzymatic assay for URO-S activity in cultured human skin fibroblasts and permits clear differentiation of AIP carrier from normal individuals.

Abortion, Induced↗

PubMed1978

Studies in porphyria. VII. Induction of uroporphyrinogen-I synthase and expression of the gene defect of acute intermittent porphyria in mitogen-stimulated human lymphocytes.

A 50% reduction in the activity of uroporphyrinogen-I (URO) synthase in liver, erythrocytes, and cultured skin fibroblasts characterizes all patients with clinically active acute intermittent porphyria (AIP). The same enzyme defect has also been demonstrated in the erythrocytes and skin fibroblasts of completely latent gene carriers of this disorder and presumably exists in the liver as well. In this study, we examined whether or not the formation of URO-synthase is impaired in AIP cells using lymphocytes treated with mitogens or infected with Epstein-Barr virus. Both mitogens (phytohemagglutinin and pokeweed mitogen) and Epstein-Barr virus induced the synthesis of URO-synthase in lymphocytes, but the induction of URO-synthase in AIP lymphocytes was only 50% as compared with that in normal lymphocytes. The impaired induction of URO-synthase in AIP lymphocytes reflects a specific gene defect because AIP lymphocytes showed normal [(3)H] thymidine uptake into DNA, [(3)H] uridine uptake into RNA, and normal delta-aminolevulinic acid (ALA) synthase, ALA-dehydratase, catalase activities, and heme content. Utilizing the same methodology, the ferrochelatase deficiency of hereditary erythropoietic protoporphyria could also be identified. The K(m) of the induced URO-synthase in AIP cells was identical to that of the enzyme in normal cells. The induced URO-synthase of mitogen-treated AIP lymphocytes was not accompanied by a concurrent enhanced level of ALA-synthase. Moreover, the URO-synthase deficiency in lymphocytes from actively ill AIP patients was not different from the level of enzyme activity when they were in clinical remission, or when compared with the enzyme activity of cells from completely latent AIP gene carriers. The results of this study indicate that the URO-synthase deficiency in AIP may be the result of a gene mutation regulating the rate of synthesis of a normal enzyme rather than a mutation causing a structural abnormality of this enzyme protein.

Acute Disease↗

PubMed1979