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ALA dehydratase porphyria

Karl E Anderson, MD, FACP
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


The porphyrias are metabolic disorders caused by altered activity of enzymes within the heme biosynthetic pathway. Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP; OMIM 612740, also called Doss porphyria and plumboporphyria) is the rarest of the inherited porphyrias, with only six documented cases reported worldwide.

ADP is an acute hepatic porphyria. It is an autosomal recessive disorder resulting from severe deficiency of ALAD, the second enzyme in the pathway of heme synthesis (figure 1). The incidence, pathophysiology, diagnosis, and treatment of ADP will be reviewed here. An overview of porphyrias is presented separately. (See "Porphyrias: An overview".)


Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP) is an acute porphyria resulting from severe ALAD deficiency that is caused by a genetic defect. The first two cases [1] and the fifth [2] were identified in Germany by Doss, and therefore the disease is referred to as Doss porphyria. It has also been termed plumboporphyria because ALAD is inhibited by lead, and lead poisoning can mimic the clinical and biochemical findings of ADP.


Enzymology — Heme synthesis defects can cause accumulation of pathogenic intermediates in red blood cell precursor and hepatic cells that leak into the plasma and cause toxicity to a variety of tissues. ALA dehydratase porphyria (ADP) is caused by severe reduction in the activity of the second enzyme in the heme biosynthetic pathway, delta-aminolevulinic acid (ALA) dehydratase (ALAD, also called porphobilinogen synthase [PBGS]; EC (figure 1). ALAD catalyzes the formation of the monopyrrole porphobilinogen (PBG) from two molecules of ALA (figure 2), the obligate heme precursor.

Relative to activities of other enzymes in the heme biosynthetic pathway, ALAD is present in vast abundance in mammalian cells. In the liver, for example, the activity of ALAD is 80- to 100-fold that of ALA synthase, the first enzyme in the heme biosynthetic pathway and the rate-limiting enzyme in the liver (figure 1 and table 1) [3]. This physiologic abundance of ALAD helps to explain why heterozygotes with half-normal ALAD activity are asymptomatic.


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Literature review current through: Sep 2016. | This topic last updated: Jan 25, 2016.
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  1. Doss M, von Tiepermann R, Schneider J, Schmid H. New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation. Klin Wochenschr 1979; 57:1123.
  2. Doss MO, Stauch T, Gross U, et al. The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany. J Inherit Metab Dis 2004; 27:529.
  3. Phillips JD, Anderson KE. The Porphyrias. In: Williams Hematology, 9th edition, Kaushansky K, Lichtman M, Prchal J, et al. (Eds), McGraw-Hill, New York 2016. p.839.
  4. Wetmur JG, Bishop DF, Cantelmo C, Desnick RJ. Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-length cDNA clone. Proc Natl Acad Sci U S A 1986; 83:7703.
  5. Jaffe EK, Martins J, Li J, et al. The molecular mechanism of lead inhibition of human porphobilinogen synthase. J Biol Chem 2001; 276:1531.
  6. Jaffe EK, Stith L. ALAD porphyria is a conformational disease. Am J Hum Genet 2007; 80:329.
  7. Inoue R, Akagi R. Co-synthesis of Human delta-Aminolevulinate Dehydratase (ALAD) Mutants with the Wild-type Enzyme in Cell-free System-Critical Importance of Conformation on Enzyme Activity-. J Clin Biochem Nutr 2008; 43:143.
  8. Granick JL, Sassa S, Kappas A. biochemical and clinical aspects of lead intoxication. In: Advances in Clinical Chemistry, Bodansky O, Latner AL (Eds), Academic Press, New York 1978. p.287.
  9. Anderson KE, Fischbein A, Kestenbaum D, et al. Plumbism from airborne lead in a firing range. An unusual exposure to a toxic heavy metal. Am J Med 1977; 63:306.
  10. Bergdahl IA, Grubb A, Schütz A, et al. Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human erythrocytes. Pharmacol Toxicol 1997; 81:153.
  11. Doss M, Laubenthal F, Stoeppler M. Lead poisoning in inherited delta-aminolevulinic acid dehydratase deficiency. Int Arch Occup Environ Health 1984; 54:55.
  12. Sassa S. ALAD porphyria. Semin Liver Dis 1998; 18:95.
  13. Wetmur JG. Influence of the common human delta-aminolevulinate dehydratase polymorphism on lead body burden. Environ Health Perspect 1994; 102 Suppl 3:215.
  14. Sassa S, Kappas A. Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone. J Clin Invest 1983; 71:625.
  15. Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinemia. Proc Natl Acad Sci U S A 1977; 74:4641.
  16. Mitchell G, Larochelle J, Lambert M, et al. Neurologic crises in hereditary tyrosinemia. N Engl J Med 1990; 322:432.
  17. Tschudy DP, Hess RA, Frykholm BC. Inhibition of delta-aminolevulinic acid dehydrase by 4,6-dioxoheptanoic acid. J Biol Chem 1981; 256:9915.
  18. Potluri VR, Astrin KH, Wetmur JG, et al. Human delta-aminolevulinate dehydratase: chromosomal localization to 9q34 by in situ hybridization. Hum Genet 1987; 76:236.
  19. Bishop TR, Miller MW, Beall J, et al. Genetic regulation of delta-aminolevulinate dehydratase during erythropoiesis. Nucleic Acids Res 1996; 24:2511.
  20. Kaya AH, Plewinska M, Wong DM, et al. Human delta-aminolevulinate dehydratase (ALAD) gene: structure and alternative splicing of the erythroid and housekeeping mRNAs. Genomics 1994; 19:242.
  21. Akagi R, Kato N, Inoue R, et al. delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations. Mol Genet Metab 2006; 87:329.
  22. Maruno M, Furuyama K, Akagi R, et al. Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria. Blood 2001; 97:2972.
  23. Mercelis R, Hassoun A, Verstraeten L, et al. Porphyric neuropathy and hereditary delta-aminolevulinic acid dehydratase deficiency in an adult. J Neurol Sci 1990; 95:39.
  24. Ishida N, Fujita H, Noguchi T, et al. Message amplification phenotyping of an inherited delta-aminolevulinate dehydratase deficiency in a family with acute hepatic porphyria. Biochem Biophys Res Commun 1990; 172:237.
  25. Ishida N, Fujita H, Fukuda Y, et al. Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria. J Clin Invest 1992; 89:1431.
  26. de Verneuil H, Doss M, Brusco N, et al. Hereditary hepatic porphyria with delta aminolevulinate dehydrase deficiency: immunologic characterization of the non-catalytic enzyme. Hum Genet 1985; 69:174.
  27. Akagi R, Shimizu R, Furuyama K, et al. Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria. Hepatology 2000; 31:704.
  28. Akagi R, Nishitani C, Harigae H, et al. Molecular analysis of delta-aminolevulinate dehydratase deficiency in a patient with an unusual late-onset porphyria. Blood 2000; 96:3618.
  29. Erskine PT, Senior N, Awan S, et al. X-ray structure of 5-aminolaevulinate dehydratase, a hybrid aldolase. Nat Struct Biol 1997; 4:1025.
  30. Akagi R, Yasui Y, Harper P, Sassa S. A novel mutation of delta-aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity. Br J Haematol 1999; 106:931.
  31. Breinig S, Kervinen J, Stith L, et al. Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase. Nat Struct Biol 2003; 10:757.
  32. Brandt A, Doss M. Hereditary prophobilinogen synthase deficiency in human associated with acute hepatic porphyria. Hum Genet 1981; 58:194.
  33. Doss M, Schneider J, Von Tiepermann R, Brandt A. New type of acute porphyria with porphobilinogen synthase (delta-aminolevulinic acid dehydratase) defect in the homozygous state. Clin Biochem 1982; 15:52.
  34. Doss M, Benkmann HG, Goedde HW. delta-Aminolevulinic acid dehydrase (porphobilinogen synthase) in two families with inherited enzyme deficiency. Clin Genet 1986; 30:191.
  35. Gross U, Sassa S, Jacob K, et al. 5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up. Clin Chem 1998; 44:1892.
  36. Gross U, Sassa S, Arndt T, Doss MO. Survival of two patients with severe delta-aminolaevulinic acid dehydratase deficiency porphyria. J Inherit Metab Dis 2001; 24:60.
  37. Thunell S, Holmberg L, Lundgren J. Aminolaevulinate dehydratase porphyria in infancy. A clinical and biochemical study. J Clin Chem Clin Biochem 1987; 25:5.
  38. Bird TD, Hamernyik P, Nutter JY, Labbe RF. Inherited deficiency of delta-aminolevulinic acid dehydratase. Am J Hum Genet 1979; 31:662.
  39. Akagi R, Inoue R, Muranaka S, et al. Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient. Br J Haematol 2006; 132:237.
  40. Fujita H, Sassa S, Lundgren J, et al. Enzymatic defect in a child with hereditary hepatic porphyria due to homozygous delta-aminolevulinic acid dehydratase deficiency: immunochemical studies. Pediatrics 1987; 80:880.
  41. Plewinska M, Thunell S, Holmberg L, et al. delta-Aminolevulinate dehydratase deficient porphyria: identification of the molecular lesions in a severely affected homozygote. Am J Hum Genet 1991; 49:167.
  42. Thunell S, Henrichson A, Floderus Y, et al. Liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase deficiency. Eur J Clin Chem Clin Biochem 1992; 30:599.
  43. Hassoun A, Verstraeten L, Mercelis R, Martin JJ. Biochemical diagnosis of an hereditary aminolaevulinate dehydratase deficiency in a 63-year-old man. J Clin Chem Clin Biochem 1989; 27:781.
  44. Sassa S, Fujita H, Doss M, et al. Hereditary hepatic porphyria due to homozygous delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes and erythrocytes. Eur J Clin Invest 1991; 21:244.
  45. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005; 142:439.
  46. http://rarediseasesnetwork.epi.usf.edu/porphyrias/centers/sinai.htm (Accessed on January 24, 2016).