Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase, the terminal enzyme of the haem biosynthetic pathway, which catalyses the insertion of iron into protoporphyrin to form haem. EPP is characterized clinically by photosensitivity to visible light commencing in childhood, and biochemically by elevated red cell protoporphyrin levels. Although the majority of papers and reviews have classified EPP as an autosomal dominant disorder, the inheritance has now been shown to be more complex, and both autosomal dominant and recessive patterns of inheritance have been demonstrated using ferrochelatase activity. Further molecular studies should clarify the exact mode of inheritance. It seems likely that in the majority of families a defective allele from the apparently normal parent will be required for disease expression, but another possibility is autosomal dominant inheritance with low clinical penetrance. Exposure to bright sunlight, for as little as a few minutes in the worst affected patients, causes burning pain in exposed skin, which may be so severe and persistent that it prevents sleep for several nights. Patients usually attempt to relieve the pain by cold water or cold compresses. Apart from sun avoidance, the mainstay of prophylactic treatment has been beta-carotene. Although the published evidence for the effectiveness of beta-carotene is impressive, no controlled trials using adequate doses have been performed to unequivocally confirm its usefulness. The most serious complication of EPP is acute hepatic failure, which is due to accumulation of protoporphyrin in the liver. If jaundice develops, a rapidly fatal outcome often follows, unless liver transplantation is undertaken. Regular monitoring of liver function and red cell porphyrin levels is advisable, but this does not always identify patients before serious liver damage has occurred. Even when patients are identified at an early stage in the development of liver disease the therapeutic options available to prevent further damage are limited, and have not been fully evaluated. The gene for ferrochelatase has been cloned, sequenced and mapped to the long arm of chromosome 18. As mutations continue to be identified, phenotype/genotype correlations should become apparent, and it may eventually be possible to identify those patients at risk of developing hepatic failure. In addition, as the basic enzymatic defect in EPP is at the level of the bone marrow stem cells, which are the target cells of choice in the development of retroviral-mediated gene transfer, definitive treatment of EPP by gene therapy is a distinct hope for the future.(ABSTRACT TRUNCATED AT 400 WORDS)