Porphyrias: Genetics


The porphyrias are a group of eight disorders of haem biosynthesis characterised by overproduction of haem precursors secondary to partial enzyme deficiencies or, in one porphyria, gain‐of‐function of the rate‐controlling enzyme of the pathway in erythroid cells. Patients suffer from acute neurovisceral attacks, always associated with overproduction of porphyrin precursors, skin lesions caused by photosensitisation by porphyrins or both together. All are inherited, apart from sporadic porphyria cutanea tarda. The three porphyrias in which acute attacks occur (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) and familial porphyria cutanea tarda are low penetrance autosomal dominant disorders and one is an X‐linked dominant disorder. All others are autosomal recessive. Most patients with erythropoietic protoporphyria, the commonest inherited cutaneous porphyria, are compound heterozygotes for a deleterious ferrochelatase mutation and a low expression ferrochelatase allele; the population frequency of the latter is a major determinant of the prevalence of erythropoietic protoporphyria.

Key Concepts:

  • The porphyrias are disorders of haem biosynthesis.

  • Each of the eight porphyrias is caused by an abnormality of a different enzyme of haem biosynthesis.

  • Each enzyme abnormality leads to overproduction of haem precursors in a specific pattern that defines the disorder.

  • Overproduction of porphyrin precursors leads to acute neurovisceral attacks which characterise the three autosomal dominant acute porphyrias and one rare recessive porphyria.

  • Overproduction of porphyrins leads to photosensitisation of the skin with either skin fragility and blisters or, when only protoporphyrin accumulates, acute painful photosensitivity.

  • All autosomal dominant porphyrias have low clinical penetrance.

  • Most patients with the commonest inherited cutaneous porphyria, erythropoietic protoporphyria, have inherited a low expression ferrochelatase allele trans to a deleterious ferrochelatase mutation.

  • The prevalence of erythropoietic protoporphyria and the proportion of families showing pseudodominant inheritance are determined by the population frequency of the low expression allele.

Keywords: porphyria; haem; autosomal dominant; autosomal recessive; penetrance; X‐linked dominant

Figure 1.

Pathway of haem biosynthesis. (HMB) also undergoes nonenzymatic cyclisation to uroporphyrinogen I, which may be converted to coproporphyrinogen I but is not metabolised further; unless UROS is deficient, less than 1% of HMB follows this route. Porphyrinogens are rapidly oxidised to porphyrins within tissues and during excretion. Alternative names for ALAD and PBGD are PBG synthase and HMB synthase respectively.

Figure 2.

Letters denote FECH alleles: A: normal; B: severe mutation and C: low expression. Arrow indicates individual with clinically overt EPP.



Bottomley SS (2004) Sideroblastic anemias. In: Greer JP, Foerster J, Lukens JN, Rogers GM, Paraskevas F and Glader GE (eds) Wintrobe's Clinical Hematology, pp. 1012–1033. Philadelphia: Lippincott Williams & Wilkins.

Bulaj ZJ, Phillips JD, Ajioka RS et al. (2000) Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 95: 1565–1571.

Clavero S, Bishop DF, Haskins ME et al. (2010) Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane mutations. Human Molecular Genetics 19: 584–596.

Deacon AC and Elder GH (2001) Front line tests for the investigation of suspected porphyria. Journal of Clinical Pathology 54: 500–507.

Desnick RJ and Astrin KH (2002) Congenital erythropoietic porphyria: advances in pathogenesis and treatment. British Journal of Haematology 117: 779–795.

Elder GH (1997) Hepatic porphyrias in children. Journal of Inherited Metabolic Disease 20: 237–246.

Elder GH, Gouya L, Whatley SD et al. (2009) The molecular genetics of erythropoietic protoporphyria. Cellular and Molecular Biology (Noisy‐le‐Grand) 55: 118–126.

Ged C, Moreau‐Gaudry F, Richard E et al. (2009) Congenital erythropoietic porphyria: mutation update and correlations between genotype and phenotype. Cellular and Molecular Biology (Noisy‐le‐Grand) 55: 53–60.

Goodwin RJ, Kell WJ, Laidler P et al. (2006) Photosensitivity and acute liver injury in myeloproliferative disorder secondary to late‐onset protoporphyria caused by deletion of a ferrochelatase gene in haematopoietic cells. Blood 107: 60–62.

Gouya L, Martin‐Schmitt C, Robreau AM et al. (2006) Contribution of a common single nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. American Journal of Human Genetics 78: 2–14.

Kontos AP, Ozog D, Bichakjian C and Lim HW (2003) Congenital erythropoietic porphyria associated with myelodysplasia presenting in a 72‐ year old man: report of a case and review of the literature. British Journal of Dermatology 48: 160–164.

Lamoril J, Puy H, Whatley SD et al. (2001) Characterisation of mutations in the CPO gene in British patients demonstrates absence of genotype–phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. American Journal of Human Genetics 68: 1130–1138.

Maruno M, Furuyama K, Akagi R et al. (2001) Highly heterogeneous nature of N‐aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria. Blood 97: 2972–2978.

Peters TJ and Beveridge A (2010) The blindness, deafness and madness of George III: psychiatric interactions. Journal of the Royal College of Physicians of Edinburgh 40: 81–85.

Phillips JD, Bergonia HA, Reilly CA et al. (2007b) A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proceedings of the National Academy of Sciences of the USA 104: 5079–5084.

Phillips JD, Steensma DP, Pulsipher MA et al. (2007a) Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans‐acting mutation causative for a human porphyria. Blood 109: 2618–2621.

Puy H, Deybach J‐C, Lamoril J et al. (1997) Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. American Journal of Human Genetics 60: 1373–1383.

Puy H, Gouya L and Deybach J‐C (2010) Porphyrias. Lancet 375: 924–937.

Tennant BC (1998) Lessons from the porphyrias of animals. Clinics in Dermatology 16: 307–315.

Whatley SD, Ducamp S, Gouya L et al. (2008) C‐terminal deletions in the ALAS2 gene lead to gain of function and cause X‐linked dominant protoporphyria without anemia or iron overload. American Journal of Human Genetics 83: 408–414.

Whatley SD, Puy H, Morgan RR et al. (1999) Variegate porphyria in Western Europe: identification of PPOX mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. American Journal of Human Genetics 65: 984–994.

Further Reading

Anderson KE, Sassa S, Bishop DF and Desnick RJ (2001) Disorders of heme biosynthesis: X‐linked sideroblastic anemia and the porphyrias. In: Scriver CL, Beaudet AL, Sly WS and Valle D (eds) The Molecular and Metabolic Basis of Inherited Disease, 8th edn, pp. 2961–3062. New York: McGraw‐Hill.

Dean G (1971) The Porphyrias: A Story of Inheritance and Environment, 2nd edn. London, UK: Pitman Medical.

Jenkins T (1996) The South African malady. Nature Genetics 13: 7–9.

Moore MR, McColl KEL, Rimington C and Goldberg A (1987) Disorders of Porphyrin Metabolism. New York: Plenum.

Rohl JCG, Warren M and Hunt D (1998) Purple Secret: Genes, ‘Madness’ and the Royal Houses of Europe. London, UK: Bantam Press.

Web Links

Aminolevulinate, delta‐, dehydratase (ALAD); Locus ID: 210. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=210

Aminolevulinate, delta‐, dehydratase (ALAD); MIM number: 125270. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?125270

Aminolevulinate, delta‐, synthase 2 (ALAS2); Locus ID: 212. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=212

Aminolevulinate, delta‐, synthase 2 (sideroblastic/hypochromic anemia) (ALAS2); MIM number: 301300. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?301300

Aminolevulinate, delta‐, synthase 2 (X‐linked dominant protoporphyria) (XLDPP); MIM number: 300752. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?300752

European porphyria network (EPNET): http://www.porphyriaeurope.com

Ferrochelatase (FECH); Locus ID: 2235. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2235

Ferrochelatase (protoporphyria) (FECH); MIM number: 177000. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?177000

Hydroxymethylbilane synthase (HMBS); Locus ID: 3145. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3145

Hydroxymethylbilane synthase (HMBS); MIM number: 176000. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?176000

Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim/

Uroporphyrinogen decarboxylase (UROD); Locus ID: 7389. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7389

Uroporphyrinogen decarboxylase (UROD); MIM number: 176100. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?176100

Uroporphyrinogen III synthase (congenital erythropoietic porphyria) (UROS); Locus ID: 7390. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7390

Uroporphyrinogen III synthase (congenital erythropoietic porphyria) (UROS); MIM number: 606938. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?606938

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Elder, George H(Sep 2010) Porphyrias: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005958.pub2]