Albertine Donker

Chapter 3 110 XLDPP results from gain-of-function mutations in ALAS2 (OMIM 301300) leading to protoporphyrin IX overproduction. 88 XLDPP is found in 29 families worldwide and ≈ 2 % (UK) to ≈10% (USA) of patients with the EPP phenotype . 87 The diminished ferrochelatase activity in the EPP variant results in reduced heme synthesis, with occasionally ringed sideroblasts, but without systemic iron overload. 89 This suggests that the iron absorption and supply in these patients match the requirement for reduced erythropoiesis. 90 Clinical presentation and diagnosis The variants EPP and XLDPP are clinically indistinguishable. The predominant clinical presentation is a painful photosensitivity, erythema, stinging and burning, beginning in childhood on sunlight exposed skin. In severe patients the liver is affected. 91 Twenty to 60% of the patients show a microcytic anemia, with a mean decrease in hemoglobin in adult male patients of 1.2 g/dL and reduced iron stores. 89 Fluorescent erythrocytes can be seen in a fresh, unstained blood smear. Free protoporphyrin is found in plasma and erythrocytes. Zn protoporphyrin is typically increased in XLDPP, due to the relative iron deficiency for the amount of protoporphyrin IX. 91 Treatment Since anemia is mild, its treatment is not warranted. 91 The therapy of EPP is focused on minimizing the harmful effects of exposure to sunlight and on managing the hepatotoxic effects of protoporphyrin. 3F. Congenital Erytropoietic Porphyria (CEP), due to defects in UROS or GATA1 Pathogenesis and epidemiology UROS (OMIM 606938) encodes uroporphyrinogen III synthase, the fourth enzyme of the heme biosynthetic pathway. CEP (OMIM 263700) is a rare autosomal genetic disease caused by defects in UROS , leading to erythroid accumulation of the non-physiological uroporphyrin I and coproporphyrin I. 91 A reduced red cell survival due to excess porphyrin in erythrocytes contributes to hemolytic anemia found in most patients with CEP. 92 To date, approximately 45 UROS mutations