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Porphyrias: Genetics

  1. George H Elder

Published Online: 15 SEP 2010

DOI: 10.1002/9780470015902.a0005958.pub2

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How to Cite

Elder, G. H. 2010. Porphyrias: Genetics. eLS. .

Author Information

  1. Cardiff University, School of Medicine, Cardiff, UK

Publication History

  1. Published Online: 15 SEP 2010

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