New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care

Abstract

Erythropoietic protoporphyria (EPP, MIM 177000) is an inherited disorder caused by a partial deficiency of ferrochelatase (FECH) which catalyses the chelation of iron into protoporphyrin to form haem. The majority of EPP patients experience solely a painful photosensitivity whereas a small number of them develop liver complications due to the accumulation of excessive amount of protoporphyrin in the liver. EPP is considered to be an autosomal dominant disorder, however, with a low clinical penetrance. To date, a total of 65 different mutations have been identified in the FECH gene of EPP patients. Among the 89 EPP patients who carry a “null allele” mutation which results in the formation of a truncated protein, 18 of them developed EPP-related liver complications. None of the 16 missense mutations identified among 19 patients on the other hand, have been associated with liver disease (P = 0.038). The allelic constellation of an overt patient consists of a mutated FECH allele and a “low expressed” normal allele and that of an asymptomatic carrier, a combination of a mutated and a normally expressed FECH allele. The identification of the “low expressed” allele is facilitated by haplotype analysis using two single nucleotide polymorphisms, −251 A/G in the promoter region and IVS1−23C/T. At the current time when only partially effective therapies are available, the disclosures of both “null allele” and the “low expression” mechanisms will improve patient management.

Conclusion While covering the important clinical aspect of erythropoietic protoporphyria, this article emphasises the latest achievements in the molecular genetics of the disorder.