Erythropoietic protoporphyria: Identification of novel mutations in the ferrochelatase gene and comparison of biochemical markers versus molecular analysis as diagnostic strategies

Background: Erythropoietic protoporphyria (EPP) results from an inherited d eficiency of the last enzyme of the heme biosynthetic pathway, ferrochelata se (FC), EPP is usually inherited in an autosomal dominant fashion, and the mutations in the FC gene on chromosome 18q21.3 detected in EPP patients ar e heterogeneous. Methods: In this study, we screened the FC gene for mutations in 12 patient s from 10 unrelated families with EPP and their familiy members using heter oduplex analysis, automated sequencing, and restriction enzyme digestion. Results:We detected 8 different mutations in these patients, including 1 mi ssense mutation, 5 frameshift mutations, and 2 splice site mutations, 6 of which are previously undescribed. Conclusions: We have established the molecular basis of EPP in 10 unrelated families, thereby providing further evidence for the heterogeneity in this : disorder. Importantly, molecular diagnosis allowed revisions in the statu s of several clinically unaffected silent mutation carriers within the fami lies. We compare the value of genetic research strategies with the combinat ion of biochemical data and clinical phenotype as diagnostic tools to confi rm a putative diagnosis in EPP.