Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes

Mol Genet Metab. 2019 Nov;128(3):320-331. doi: 10.1016/j.ymgme.2018.11.012. Epub 2018 Nov 30.


The inborn errors of heme biosynthesis, the Porphyrias, include eight major disorders resulting from loss-of-function (LOF) or gain-of-function (GOF) mutations in eight of the nine heme biosynthetic genes. The major sites of heme biosynthesis are the liver and erythron, and the underlying pathophysiology of each of these disorders depends on the unique biochemistry, cell biology, and genetic mechanisms in these tissues. The porphyrias are classified into three major categories: 1) the acute hepatic porphyrias (AHPs), including Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), and 5-Aminolevlulinic Acid Dehydratase Deficient Porphyria (ADP); 2) a hepatic cutaneous porphyria, Porphyria Cutanea Tarda (PCT); and 3) the cutaneous erythropoietic porphyrias, Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EPP), and X-Linked Protoporphyria (XLP). Their modes of inheritance include autosomal dominant with markedly decreased penetrance (AIP, VP, and HCP), autosomal recessive (ADP, CEP, and EPP), or X-linked (XLP), as well as an acquired sporadic form (PCT). There are severe homozygous dominant forms of the three AHPs. For each porphyria, its phenotype, inheritance pattern, unique genetic principles, and molecular genetic heterogeneity are presented. To date, >1000 mutations in the heme biosynthetic genes causing their respective porphyrias have been reported, including low expression alleles and genotype/phenotype correlations that predict severity for certain porphyrias. The tissue-specific regulation of heme biosynthesis and the unique genetic mechanisms for each porphyria are highlighted.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biosynthetic Pathways / genetics*
  • Gain of Function Mutation
  • Gene Expression Regulation
  • Heme / metabolism*
  • Humans
  • Loss of Function Mutation
  • Penetrance*
  • Porphobilinogen Synthase / deficiency
  • Porphobilinogen Synthase / genetics
  • Porphyria, Acute Intermittent / genetics
  • Porphyrias / classification
  • Porphyrias / genetics*
  • Porphyrias, Hepatic / genetics
  • Protoporphyria, Erythropoietic / genetics


  • Heme
  • Porphobilinogen Synthase

Supplementary concepts

  • Porphyria, Acute Hepatic