Partial deficiency of enzymes in the haem synthetic pathway gives rise to a 
group of seven inherited metabolic disorders, the porphyrias. Each deficiency is 
associated with a characteristic increase in haem precursors that correlates 
with the symptoms associated with individual porphyrias and allows accurate 
diagnosis. Two types of clinical presentation occur separately or in 
combination; acute life-threatening neurovisceral attacks and/or cutaneous 
symptoms. Five of the porphyrias are low-penetrance autosomal dominant 
conditions in which clinical expression results from additional factors that act 
by increasing demand for haem or by causing an additional decrease in enzyme 
activity or by a combination of these effects. These include both genetic and 
environmental factors. In familial porphyria cutanea tarda (PCTF), environmental 
factors that include alcohol, exogenous oestrogens and hepatotropic viruses 
result in inhibition of hepatic enzyme activity via a mechanism that involves 
excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance 
of a functional polymorphism in trans to a null ferrochelatase allele accounts 
for most clinically overt cases. In the autosomal dominant acute hepatic 
porphyrias (acute intermittent porphyria, variegate porphyria, hereditary 
coproporphyria), acute neurovisceral attacks occur in a minority of those who 
inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) 
and endogenous factors (e.g. hormones) have been identified as provoking acute 
attacks, these do not provide a full explanation for the low penetrance of these 
disorders. It seems probable that genetic background influences susceptibility 
to acute attacks, but the genes that are involved have not yet been identified.