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.