New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation

Doss, M.; Tiepermann, R. v.; Schneider, Jürgen; He, Schmid

doi:10.1007/bf01481493

Cited by 142 publications

(78 citation statements)

References 19 publications

(20 reference statements)

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“…The occurrence of AIP-like neurological symptoms in certain hereditary tyrosinemia patients suggests, however, that PBG or its derivative porphobilin are not likely to be the cause of the neurotoxicity in these diseases because ALA dehydratase in the tissues of hereditary tyrosinemia is profoundly inhibited and patients excrete excessive amounts of ALA, rather than PBG. In this respect it is also of considerable interest that an AIP-like syndrome has been recently described in a family with a hereditary deficiency of ALA dehydratase (41). These observations suggest that the neurovisceral manifestations of AIP, and of hereditary tyrosinemia, may all be related to ALA, or perhaps some metabolic derivative of this compound, rather than to other sequential intermediates, i.e., PBG or porphyrins, in the heme pathway.…”

Section: Discussionmentioning

confidence: 97%

Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Sassa¹,

Kappas²

1983

J. Clin. Invest.

131

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A B S T R A C T Succinylacetone (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase. It is known that patients with this hereditary disease excrete excessive amounts of b-aminolevulinic acid (ALA) in urine and that certain patients have an accompanying clinical syndrome resembling that of acute intermittent porphyria (AIP). In order to elucidate the relation of succinylacetone to the heme biosynthetic pathway, we have examined the effects of this metabolite on the cellular heme content of cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse and bovine liver. Our data indicate that succinylacetone is an extremely potent competitive inhibitor of ALA dehydratase in human as well as in animal tissues. By using purified preparations of the enzyme from human erythrocytes and mouse and bovine liver, an inhibitor constant ranging from 2 X 1O-7 M to 3 X 1O-7 M was obtained. In cultured hepatocytes, succinylacetone also inhibited ALA dehydratase activity, decreased the cellular content of heme and cytochrome P-450, and greatly potentiated the induction response of ALA synthase to drugs such as phenobarbital, chemicals such as allylisopropylacetamide and 3,5-dicarbethoxy-1,4-dihydrocollidine, and natural steroids such as etiocholanolone. Four patients with hereditary tyrosinemia have been studied and all were found to have greatly depressed levels of erythrocyte ALA dehydratase activity and elevated concentrations of this inhibitor in urine. These findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone, an abnormal product of the tyrosine metabolic pathway,

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Section: Discussionmentioning

confidence: 97%

Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Sassa¹,

Kappas²

1983

J. Clin. Invest.

131

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“…AIP is a dominant porphyria due to half-normal levels of the third enzyme in the heme biosynthesis pathway. Furthermore, affected individuals with the recessive ALAD-deficient porphyria manifest chronic neurologic manifestations (20)(21)(22). Finally, asymptomatic heterozygotes for the latter porphyria develop acute lead poisoning when exposed to low levels of lead (23,24).…”

Section: Introductionmentioning

confidence: 99%

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Wetmur

1994

Environ Health Perspect

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&Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD2 allele. Human ALAD1 and ALAD2 cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD allele have blood-lead levels about 10 pg/dl greater than similarly exposed individuals carrying only the ALAD1 allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man. -Environ Health Perspect 102(Suppl 3): 215-219 (1994)

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“…Acute hepatic porphyric syndrome linked to a porphobilinogen synthase deficiency was first reported by Doss et al (4) in two young patients who prescnted with an activity of this enzyme below l % of the value of normal control subjects. Since then, two other cases have been dcscribed in the literature.…”

Section: Discussionmentioning

confidence: 91%

Deficiency of Porphobilinogen Synthase Associated with Acute Crisis. Diagnosis of the First Two Cases in Chile by Laboratory Methods

Wolff

Piderit²,

Armas-Merino³

1991

Clinical Chemistry and Laboratory Medicine

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Summary: Erythrocyte porphobilinogen synthase deficiency was confirmed by the determination of its activity in blood and also by the high levels of both porphyrins and 5-aminolaevulinic acid in the urine of two siblings. jThey presented with a picture of porphyric attack characterized by abdominal colic pain, high blood pressure, jtachycardia and severe constipation. The profile of both porphyrins and their precursors in urine and blood •resembled lead poisoning. However, this was mied out because both patients had normal-blood levels of lead. Furthennore, porphobilinogen synthase activity did not normalize when it was determined in the presence of dithiothreitol or dithiothreitol plus zinc chloride. No other causes to account for a deficiency in porphobilinogen synthase activity were identified.The simultaneous occurrence of similar clinical and biochemical Symptoms suggests that the same triggering factor was present. Because the activity of porphobilinogen synthase was less than 4% of normal values, it is possible that these patients were homozygotes with respect to this defect, which could explain the presence of clinical Symptoms. We propose that this metabolic defect is not uncommon and it should be kept in mind when diagnosing of porphyrias or heavy metal intoxications.

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New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation

Cited by 142 publications

References 19 publications

Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Hereditary Tyrosinemia and the Heme Biosynthetic Pathway. PROFOUND INHIBITION OF δ-AMINOLEVULINIC ACID DEHYDRATASE ACTIVITY BY SUCCINYLACETONE

Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden.

Deficiency of Porphobilinogen Synthase Associated with Acute Crisis. Diagnosis of the First Two Cases in Chile by Laboratory Methods

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