Variable phenotypic expression of genotypic abnormalities in the porphyrias.

The inherited porphyrias are the consequence of inherited deficiencies of enzymes in the heme synthesis pathway; they exhibit classical Mendelian inheritance patterns. The acute porphyrias (acute intermittent, porphyria variegata, hereditary coproporphyria) result from 50% (approx.) deficiencies of specific enzymes, which demonstrate autosomal dominant inheritance. However, only approx. 10% of subjects who inherit a porphyrin enzyme deficiency develop the corresponding acute porphyria and in most instances there is no obvious reason why one patient with an enzyme deficiency is symptomatic whereas another is not. Control of heme synthesis is achieved by the repressor effect of heme on the enzyme ALA synthase. Acute attacks of porphyria can be precipitated in susceptible persons by drugs, ethanol, starvation, hormones, stress and infection. The mechanism is usually by induction of ALA synthase activity. The molecular biology of porphyria variegata and hereditary coproporphyria is large unexplored. Acute intermittent porphyria is due to a partial deficiency of the enzyme porphobilinogen deaminase in the liver. The location of the gene for this enzyme has been identified on the long arm of chromosome 11. Acute intermittent porphyria is a genetically heterogenous disease with the abnormality frequently being a point mutation affecting synthesis of the enzyme.