Inherited Disorders of Haem Synthesis:

The Human Porphyrias
Part of the Molecular Biology Intelligence Unit book series (MBIU)


The porphyrias are inherited metabolic disorders resulting from partial deficiency of enzymes of the haem biosynthetic pathway. Each particular enzyme deficiency gives rise to increased levels of metabolites prior to the pathway blockage, which result in characteristic clinical features, and allow the individual conditions to be diagnosed. The acute neurovisceral attacks, which are common to ALA dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria are the result of neuronal damage by a mechanism which involves accumulation of ALA. Cutaneous manifestations comprise either bullous lesions (fragile skin, blisters), which are common to congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), VP and HCP, or acute photosensitivity which is associated with erythropoietic protoporphyria (EPP). Skin lesions result from photoactivation of circulating porphyrins by light (400–410 nm) resulting in the generation of free oxygen radicals with the different presentations explained by the physicochemical properties of the individual porphyrins. All the porphyrias, apart from the sporadic form of PCT, are inherited either as autosomal dominant (AIP, HCP, PCT, VP, EPP) or autosomal recessive (ADP, CEP) disorders. The molecular genetics of each disorder has been fully characterised and investigation at the DNA level is now indispensable in management of families as it allows accurate presymptomatic testing, and genetic counselling. The mainstay of management remains prevention, either by avoiding sunlight in the case of the cutaneous porphyrias or, in the acute porphyrias, factors such as prescribed drugs which are known to precipitate acute attacks. For severely affected patients newly developed treatments include liver transplantation (in AIP) and bone marrow transplantation in CEP Active research is underway to develop enzyme replacement for AIP and gene therapy for the erythropoietic porphyrias.


Porphyria Cutanea Tarda Acute Intermittent Porphyria Porphobilinogen Deaminase Acute Porphyria Variegate Porphyria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Warren MJ, Jay M, Hunt DM et al. The maddening business of King George III and porphyria. Trends Biochem Sci 1996; 21:229–234.PubMedGoogle Scholar
  2. 2.
    Loftus LS, Arnold WN. Vincent van Gogh’s illness: Acute intermittent porphyria? BMJ 1991; 303:1589–1591.CrossRefPubMedGoogle Scholar
  3. 3.
    Anderson KE, Sassa S, Bishop DF et al. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Scriver CR, Beaudet AL, Sly WS et al, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2961–3062.Google Scholar
  4. 3b.
    Whatley SD, Ducamp S, Gouya L et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause a previously undefined type of human porphyria, X-linked dominant protoporphyria, without anemia or iron overload. Am J Human Genet 2008; 83:408–414.CrossRefGoogle Scholar
  5. 4.
    Ponka P. Cell biology of heme. Am J Med Sci 1999; 318:241–256.CrossRefPubMedGoogle Scholar
  6. 5.
    Elder GH, Hift RJ, Meissner PJ. The acute porphyrias. Lancet 1997; 349:1613–2161.CrossRefPubMedGoogle Scholar
  7. 6.
    Millward LM, Kelly P, Deacon A et al. Self-rated psychosocial consequences and quality of life in the acute porphyrias. J Inherit Metab Dis 2001; 24:733–747.CrossRefPubMedGoogle Scholar
  8. 7.
    Andant C, Puy H, Bogard C et al. Hepatocellular carcinoma in patients with acute hepatic porphyria: Frequency of occurrence and related factors. J Hepatol 2000; 32:933–939.CrossRefPubMedGoogle Scholar
  9. 8.
    Andersson C, Wikberg A, Stegmayr B et al. Renal symptomatology in patients with acute intermittent porphyria. A population-based study. J Intern Med 2000; 248:319–325.CrossRefPubMedGoogle Scholar
  10. 9.
    Meerman L. Erythropoietic protoporphyria. An overview with emphasis on the liver. Scand J Gastroenterol Suppl 2000; 232:79–85.PubMedGoogle Scholar
  11. 10.
    Mauzerall D, Granick S. The occurrence and determination of δ-aminolaevulinate and porphobilinogen in urine. J Biol Chem 1956; 219:435–446.PubMedGoogle Scholar
  12. 11.
    Deacon AC, Elder GH. Front line tests for the investigation of suspected porphyria. J Clin Pathol 2001; 54:500–507.CrossRefPubMedGoogle Scholar
  13. 12.
    Whatley SD, Puy H, Morgan RR et al. Variegate porphyria in Western Europe: Identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet 1999; 65:984–994.CrossRefPubMedGoogle Scholar
  14. 13.
    Lamoril J, Puy H, Whatley SD et al. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am J Hum Genet 2001; 68:1130–1138.CrossRefPubMedGoogle Scholar
  15. 14.
    Whatley SD, Woolf JR, Elder GH. Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: Identification of 25 novel mutations. Hum Genet 1999; 104:505–510.CrossRefPubMedGoogle Scholar
  16. 15.
    Nordmann Y, Puy H, DaSilva V et al. Acute intermittent porphyria: Prevalence of mutations in the porphobilinogen deaminase gene in blood donors in France. J Int Med 1997; 242:213–217.CrossRefGoogle Scholar
  17. 16.
    Kauppinen R, Mustajoki P. Prognosis of acute porphyria: Occurrence of acute attacks, precipitating factors, and associated diseases. Medicine 1992; 71:1–13.PubMedGoogle Scholar
  18. 17.
    Andersson C, Floderus Y, Wikberg A et al. The W198X and R173W mutations in the porphobilinogen deaminase gene in acute intermittent porphyria have higher clinical penetrance than R167W. A population based study. Scand. J Clin Lab Invest 2000; 60:643–648.CrossRefGoogle Scholar
  19. 18.
    Meissner PN, Dailey TA, Hift RJ et al. A R59W mutation in human protoporphyrinogen oxidase results in decreased activity and is prevalent in South Africans with variegate porphyria. Nat Genet 1996; 13:95–97.CrossRefPubMedGoogle Scholar
  20. 19.
    Lee JS, Anvret M. Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria. Proc Nad Acad Sci USA 1991; 88:10912–10915.CrossRefGoogle Scholar
  21. 20.
    Elder GH. Hepatic porphyrias in children. J Inher Metab Dis 1997; 20:237–246.CrossRefPubMedGoogle Scholar
  22. 21.
    Lamoril J, Puy H, Gouya L et al. Neonatal anaemia due to inherited harderoporphyria: Clinical characteristics and molecular basis. Blood 1998; 91:1453–1457.PubMedGoogle Scholar
  23. 22.
    Gouya L, Puy H, Robreau AM et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet 2002; 30:27–28.CrossRefPubMedGoogle Scholar
  24. 23.
    Cox TM. Protoporphyria. In: Kadish KM, Smith KM, Guilard R, eds. The Porphyrin Handbook, vol. 14, Medical aspects of porphyrias. Amsterdam: Academic Press, 2003:121–150.Google Scholar
  25. 24.
    Chen FP, Risheg H, Liu Y et al. Ferrochelatase gene mutations in erythropoietic protoporphyria: Focus on liver disease. Cell Mol Biol 2002; 48:83–89.PubMedGoogle Scholar
  26. 25.
    Elder GH. Porphyria cutanea tarda and related disorders. In: Kadish KM, Smith KM, Guilard R, eds. The Porphyrin Handbook: Vol. 14 Medical Aspects of Porphyrins. San Diego: Academic Press, 2003:67–92.Google Scholar
  27. 26.
    Bulaj ZJ, Phillips JD, Ajioka RS et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000; 95:1565–1571.PubMedGoogle Scholar
  28. 27.
    Phillips JD, Jackson LK, Bunting M et al. A mouse model of familial porphyria cutanea tarda. Proc Natl Acad Sci USA 2001; 98:259–264.CrossRefPubMedGoogle Scholar
  29. 28.
    Franklin MR, Phillips JD, Kushner JP. Uroporphyria in the uroporphyrinogen decarboxylase-deficient mouse: Interplay with siderosis and polychlorinated biphenyl exposure. Hepatology 2002; 36:805–811.PubMedGoogle Scholar
  30. 29.
    Sinclair PR, Gorman N, Trask HW et al. Uroporphyria caused by ethanol in Hfe(-/-) mice as amodel for porphyria cutanea tarda. Hepatology 2003; 37:351–358.CrossRefPubMedGoogle Scholar
  31. 30.
    Desnick RJ, Astrin KH. Congenital erythropoietic porphyria: Advances in pathogenesis and treatment. Br J Haem 2002; 117:779–795.CrossRefGoogle Scholar
  32. 31.
    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; 30:599–606.PubMedGoogle Scholar
  33. 32.
    Meissner PN, Adams P, Kirsch R. Allosteric inhibition of human lymphoblasts and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen: A possible mechanism for the acute attack of variegate porphyria. J Clin Invest 1993; 91:1436–1444.CrossRefPubMedGoogle Scholar
  34. 33.
    Meyer UA, Schuurmans MM, Lindberg RLP. Acute porphyrias: Pathogenesis of neurological manifestations. Sem Liv Dis 1998; 18:43–52.CrossRefGoogle Scholar
  35. 34.
    Lindberg RLP, Porcher C, Grandchamp B et al. Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria. Nat Genet 1996; 12:195–199.CrossRefPubMedGoogle Scholar
  36. 35.
    Lindberg RLP, Martini R, Baumgartner M et al. Motor neuropathy in porphobilinogen deaminase-defient mice imitates the peripheral neuropathy of human acute porphyria. J Clin Invest 1999; 103:1127–1134.CrossRefPubMedGoogle Scholar
  37. 36.
    Sandberg S, Brun A. Light-induced protoporphyrin release from erythrocytes in erythropoietic protoporphyria. J Clin Invest 1982; 70:693–698.CrossRefPubMedGoogle Scholar
  38. 37.
    Andant C, Puy H, Bogard C et al. Hepatocellular carcinoma in patients with acute hepatic porphyria: Frequency of occurrence and related factors. J Hepatol 2000; 32:933–939.CrossRefPubMedGoogle Scholar
  39. 38.
    Minder EI, Gouya L, Schneider-Yin X et al. A genotype-phenotype correlation between null-allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria. Cell Mol Biol (Noisy-le-grand) 2002; 48:90–96.Google Scholar
  40. 39.
    Badminton MN, Elder GH. Management of acute and cutaneous porphyrias. Int J Clin Pract 2002; 56:272–278.PubMedGoogle Scholar
  41. 40.
    Elder GH, Hift RJ. Treatment of acute porphyria. Hospital Medicine 2001; 62:422–425.PubMedGoogle Scholar
  42. 41.
    Mustajoki P, Nordmann Y. Early administration of haem arginate for acute porphyric attacks. Arch Intern Med 1993; 153:2004–2008.CrossRefPubMedGoogle Scholar
  43. 42.
    Poh-Fitzpatrick MB, Wang X, Anderson KE et al. Erythropoietic protoporphyria: Altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations. J Am Acad Dermatol 2002; 46:861–866.CrossRefPubMedGoogle Scholar
  44. 43.
    Soonawalla ZF, Orug T, Badminton MN et al. Liver Transplantation as a cure for acute intermittent porphyria. Lancet 2004; 363:705–756.CrossRefPubMedGoogle Scholar
  45. 44.
    Wiesner RH, Ralela J, Ishitani MB et al. Recent advances in liver transplantation. Mayo Clin Proc 2003; 78:197–210.CrossRefPubMedGoogle Scholar
  46. 45.
    Meerman L, Verwer R, Slooff MJ et al. Perioperative measures during liver transplantation for erythropoietic protoporphyria. Transplantation 1994; 88:541–549.Google Scholar
  47. 46.
    Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 2003; 3:477–488.CrossRefPubMedGoogle Scholar
  48. 47.
    Geronimi F, Richard E, Lamrissi-Garcia I et al. Lentivirus-mediated gene transfer of uroporphyrinogen III synthase fully corrects the porphyric phenotype in human cells. J Mol Med 2003; 81:310–320.PubMedGoogle Scholar
  49. 48.
    Pawliuk R, Bachelot T, Wise RJ et al. Long-term cure of the photosensitivity of murine erythropoietic protoporphyria by preselective gene therapy. Nat Med 1999; 7:768–772.Google Scholar
  50. 49.
    Fontanellas A, Mazurier F, Moreau-Gaudry F et al. Correction of uroporphyrinogen decarboxylase deficiency (Hepatoerythropoietic porphyria) in Epstein-Barr virus-transformed B-cell lines by retrovirus-mediated gene transfer: Fluorescence-based selection of transduced cells. Blood 1999; 94:465–474.PubMedGoogle Scholar
  51. 50.
    Raper SE, Yudkoff M, Chirmule N et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 2002; 13:163–175.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Department of Medical Biochemistry and Immunology, School of MedicineCardiff UniversityCardiffUK

Personalised recommendations