Porphyrias: Genetics

Abstract

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. Hydroxymethylbilane (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.

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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

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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]