Objectives: Erythropoietic protoporphyria (EPP) is a genetic disorder in which deficient ferrochelatase (FECH) activity causes the excessive production and excretion of protoporphyrin. This in turn causes the major clinical manifestation of EPP, photosensitivity and, in some patients, hepatobiliary disease that may be severe. The objective of this study was to define genotypic determinants of phenotype in EPP.
Methods: FECH activity was measured in 30 tissue samples from 26 patients with symptomatic EPP to determine the degree of deficient activity. FECH DNA analysis was also done in 26 families with EPP to identify mutations and examine for the presence of a polymorphism (IVS3-48c) that causes low gene expression.
Results: The level of residual FECH activity that was measured in tissue samples of patients with symptomatic EPP was <or=30% of the mean normal level in all patients except one. Lowest levels (4-20% normal) were in patients with advanced EPP liver disease. Heterozygous FECH mutations were found in 45 individuals from 26 families with EPP. In 94% of the 32 symptomatic individuals, 15 of whom had liver disease, the polymorphism was present in the nonmutant allele. In 13 asymptomatic patients, the polymorphism was absent.
Conclusions: Patients with symptomatic EPP (photosensitivity with/without hepatobiliary disease) usually have a mutation in 1 FECH allele that alters enzyme structure/function, together with a polymorphism in the nonmutant allele that causes low gene expression. This leads to a significant reduction in FECH activity that causes symptomatic disease to develop because of the excess protoporphyrin produced.