Abstract

AIM:

To review our present knowledge about the molecular genetics of erythropoietic protoporphyria.

METHODS:

Literature review.

RESULTS:

Erythropoietic protoporphyria (EPP) is caused by decreased activity of the enzyme ferrochelatase and is characterized by distressing photosensitivity commencing in childhood. For reasons that are not yet fully understood, some patients develop potentially fatal acute hepatic failure. The gene for ferrochelatase has been cloned, sequenced and mapped to the long arm of chromosome 18. Subsequent molecular analysis has shown EPP to be very genetically heterogeneous, and 28 different mutations in 31 unrelated patients have been published. No mutation(s) in the ferrochelatase gene or elsewhere in the genome, or environmental factors have been conclusively associated with the development of protoporphyric hepatic failure. The complex inheritance of EPP has now been partially resolved. In the majority of families co-inheritance of a mutant ferrochelatase allele from one parent and a low-output 'normal' ferrochelatase allele from the other parent is required for disease expression. Gene therapy experiments have been completed in-vitro and are in progress in an animal model of EPP.

CONCLUSION:

EPP is a good example of how advances in molecular biology have led to a greater understanding of the pathogenesis and inheritance of disease. The most urgent need is to discover why some EPP patients develop hepatic failure. Gene therapy of EPP patients should become possible in the future.