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Persistent protoporphyrinemia in hereditary porphobilinogen synthase (δ-aminolevulinic acid dehydrase) deficiency under low lead exposure

Persistierende Protoporphyrinämie bei hereditärem Porphobilinogen-Synthase-(δ-Aminolävulinsäure-Dehydrase)-Mangel unter geringgradiger Blei-Exposition

A new molecular basis for the pathogenesis of lead intoxication

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Summary

For several years, a 4–12-fold increase of the upper normal limit in erythrocyte protoporphyrin concentrations persisted in two men 34 and 39 years of age who were chronically exposed to lead. We are dealing with a zinc protoporphyrinemia in both cases, without lead intoxication or anemia. The 34-year-old had been a regular blood donor for 10 years and had already been treated for iron deficiency several times. Hemoglobin, red cell counts, hematocrit, and iron were at the lower normal limit. The activity of porphobilinogen synthase (PBG-S), uroporphyrinogen-synthase and -decarboxylase as well as urinary porphyrin precursors and porphyrin excretion were normal. Protoporphyrinemia was said to be due to a prelatent/latent iron deficiency.

In the 39-year-old, the activity of PBG-S was lowered to 388 µmol/l·h, as compared to the mean of controls (1,190±210,x±SD,n=50), in connection with a slightly elevated excretion of δ-aminolevulinic acid and coproporphyrin in the urine and a high-normal blood lead level. In his family there was no history of either a protoporphyrinemia or a hematological disturbance. Six of eight family members in three generations showed a diminished activity of PBG-S: 600±160,P<0.001 compared to controls. These family members are heterozygous with regard to the PBG-S deficiency; they are clinically unobtrusive in comparison to homozygotes with an acute prophyria syndrome. Activation by zinc and reactivation by dithiothreitol were normal in contrast to PBG-S from patients with lead intoxication. The cause of biochemical symptoms of subclinical lead intoxication developed by the propositus is probably due to the hereditary PBG-S deficiency which sensitizes him to low-level lead exposure. The determination of red cell PBG-S activity can be recommended as a test detecting heterozygotes.

The hereditary PBG-S deficiency is recognized as a new molecular basis for the pathogenesis of lead intoxication.

Zusammenfassung

Bei zwei Blei-exponierten Männern im Alter von 34 und 39 Jahren persistierte eine erhöhte Konzentration des Erythrozyten-Protoporphyrins um das Vier- bis Zwölffache der oberen Normgrenze über mehrere Jahre. Es handelt sich um eine Zink-Protoporphyrinämie, ohne daß eine Bleiintoxikation oder Anämie vorlag. Der 34jährige hatte sich über zehn Jahre regelmäßig als Blutspender zur Verfügung gestellt und war mehrfach schon wegen Eisenmangel behandelt worden. Hämoglobin, Erythrozytenzahl, Hämatokrit und Eisen lagen an der unteren Normgrenze; die Aktivitäten der Porphobilinogen-Synthase (PBG-S), Uroporphyrinogen-Synthase und -Decarboxylase in Erythrozyten sowie die Porphyrinvorläufer- und Porphyrinausscheidung im Urin war normal. Die Protoporphyrinämie wurde auf einen prälatenten/latenten Eisenmangel zurückgeführt.

Bei dem 39jährigen hingegen war die Aktivität der PBG-S auf 388 µmol/l·h gegenüber dem Mittelwert der Kontrollen (1 190±210,x±SD,n=50) herabgesetzt, begleitet von einer geringgradig erhöhten Ausscheidung von δ-Aminolävulinsäure und Koproporphyrin im Urin und einer hochnormalen Bleikonzentration im Blut. Bei seinen Familienangehörigen fand sich weder eine Protoporphyrinämie noch eine hämatologische Störung. Sechs von acht Familienmitgliedern in drei Generationen wiesen eine erniedrigte Aktivität der PBG-S auf: 600±160;p<0,001 verglichen zu Kontrollen. Diese Familienmitglieder sind heterozygot in bezug auf den PBG-S-Mangel; sie sind klinisch unauffällig im Vergleich zu Homozygoten mit einem akuten Porphyrie-Syndrom. Die Zink-Aktivierung des Enzyms und seine Reaktivierung durch Dithiothreitol waren normal im Gegensatz zur PBG-S von Patienten mit Bleivergiftung. Die Ursache der biochemischen Symptome einer subklinischen Bleiintoxikation bei dem Propositus wird in dem hereditären PBG-S-Defekt gesehen, der ihn für eine niedrige Bleiexposition sensibilisiert. Die Bestimmung der PBG-S wird zur Entdeckung Heterozygoter empfohlen.

Als neue molekulare Basis für die Pathogenese der Bleiintoxikation wird der hereditäre PBG-S-Mangel erkannt.

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Authors and Affiliations

  1. Clinical Biochemistry the Faculty of Medicine at the University of Marburg, Germany

    M. Doss, U. Becker, F. Sixel & S. Geisse

  2. Department of Neurology, the Faculty of Medicine at the University of Marburg, Germany

    H. Solcher

  3. Medical Policlinic of the Faculty of Medicine at the University of Marburg, Germany

    J. Schneider

  4. Occupational Medical Service of Daimler-Benz, Sindelfingen

    G. Kufner & H. Schlegel

  5. Institute of Chemistry, Applied Physical Chemistry, Nuclear Research Centre (KFA), Jülich

    M. Stoeppler

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  1. M. Doss
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  2. U. Becker
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Additional information

This study has been supportec by the Deutsche Forschungsgemeinschaft (German Research Association, Grant Do 134/10), Bonn-Bad Godesberg

This work is dedicated to Prof. Dr. Rudolf Gross on the occasion of his 65th birthday

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Doss, M., Becker, U., Sixel, F. et al. Persistent protoporphyrinemia in hereditary porphobilinogen synthase (δ-aminolevulinic acid dehydrase) deficiency under low lead exposure. Klin Wochenschr 60, 599–606 (1982). https://doi.org/10.1007/BF01711435

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  • DOI: https://doi.org/10.1007/BF01711435

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