Variability in Erythrocyte and Plasma Porphyrin Levels in Erythropoietic Protoporphyria and X-Linked Protoporphyria

Introduction: Erythropoietic protoporphyria (EPP), the most common porphyria in children and the third most common in adults, results from mutations of ferrochelatase (FECH), which catalyzes ferrous iron insertion into protoporphyrin IX to complete heme synthesis. X-linked protoporphyria (XLP) is less common, has the same clinical phenotype, and is due to gain of function mutations of erythroid δ-aminolevulinic acid synthase (ALAS2). Both result in accumulation of protoporphyrin and painful, non-blistering cutaneous photosensitivity that profoundly affects quality of life, and can be complicated by life-threatening hepatopathy. Information on variability in porphyrin levels and photosensitivity in the absence of hepatopathy is limited. Methods: We studied 195 subjects (109 males, 87 females, 10 months to 75 years of age) with typical nonblistering photosensitivity. EPP or XLP was confirmed biochemically by the University of Texas Medical Branch at Galveston Porphyria Laboratory, and in most by identification of FECH or ALAS2 mutations at the Mt. Sinai Porphyria Center. Those not yet DNA tested were classified as EPP (56 subjects) or XLP (1 subject) by the proportions of erythrocyte metal-free and zinc protoporphyrin. Subjects with protoporphyric hepatopathy, which further increases porphyrin levels, were excluded. Levels were repeated over time to determine variability, and individuals with the same mutations were compared. Results: Differences in total erythrocyte protoporphyrin between subjects exceeded variation within subjects over time (p<0.0001), which was greater with longer follow-up. Erythrocyte porphyrin levels were higher and less variable over time than plasma porphyrins, suggesting lack of equilibrium. Porphyrin levels on average and the proportion of zinc protoporphyrin were higher in the 15 subjects with XLP and ALAS2 mutations (12 families with 3 different mutations) than in the 178 subjects with EPP and FECH mutations (79 families with 22 different mutations, p<0.0004). Differences in erythrocyte porphyrin levels among unrelated subjects with different FECH or ALAS2 mutations were significantly greater than among those who shared the same mutations. Conclusion: Defining variability in erythrocyte and plasma porphyrins is important for assessing photosensitivity and risk for hepatopathy in EPP and XLP. In XLP, protoporphyrin is higher on average and zinc protoporphyrin is consistently higher than in EPP. Individual differences were smaller in patients with the same mutations, suggesting genotype-phenotype correlation.