LAUSR

Congenital erythropoietic porphyria (CEP, MIM 263700) is a rare autosomal recessive disease caused by impaired activity of uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. Accumulation of porphyrins in red blood cells, mainly uroporphyrinogen I (URO I) and coproporphyrinogen I (COPRO I), leads to ineffective erythropoiesis and chronic hemolysis. Porphyrin deposition in the skin is responsible for severe photosensitivity resulting in bullous lesions and progressive photomutilation. Treatment options are scarce, relying mainly on supportive measures and, for severe cases, on bone marrow transplantation (BMT). Increased activation of the heme biosynthetic pathway by gain-of-function mutations in ALAS2, the first and rate-limiting enzyme, results in a more severe phenotype. Iron deficiency promotes the binding of iron regulatory protein to the 5’ untranslated region iron-responsive elements of ALAS2 mRNA and therefore decreases its translation. Egan et al. observed a 32-year-old woman with CEP who exhibited spontaneous improvement in photosensitivity and hemolysis after chronic gastrointestinal bleeding that resulted in iron deficiency. They treated her with an iron chelator, resulting in correction of the hemolysis, decreased porphyrin levels and improved quality of life with reduced photosensitivity. We recently identified three CEP siblings with phenotypes ranging from moderate to asymptomatic which were modulated by iron availability, highlighting the importance of iron metabolism in the disease. Based on these data, we prospectively treated a CEP patient with phlebotomies to investigate the feasibility, safety and efficacy of this treatment. We observed discontinuation of hemolysis and a marked decrease in plasma and urine porphyrins. The patient reported a major improvement in photosensitivity. Finally, erythroid cultures were performed, demonstrating the role of iron in the rate of porphyrin production. The study was conducted in accordance with the World Medical Association Declaration of Helsinki ethical principles for medical research involving human subjects. A 49-year-old Caucasian female was treated for CEP by repeated phlebotomies for almost 2 years. She was diagnosed with CEP at the age of 25 after experiencing symptoms since the age of 4, including photosensitivity with skin fragility, blistering and scarring, mouth lesions with