Porphyrias

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 disorder. All others are autosomal recessive. Enzyme activities in the autosomal recessive porphyrias and in the homozygous variants of other porphyrias are usually less than 20% of normal.

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 that 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 pseudo‐dominant 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 non‐enzymatic 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 alleles: A, normal; B, severe mutation and C, low expression. Arrow indicates individual with clinically overt EPP.
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Further Reading

Balwani M and Desnick RJ (2012 Nov 29); The porphyrias: advances in diagnosis and treatment. Blood 120 (23): 4496–4504.

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Besur, Siddesh, and Bonkovsky, Herbert L(Feb 2015) Porphyrias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000565.pub3]