Albertine Donker

Rare Inherited Iron and Heme-related Anemias 109 3 3D. Sideroblastic anemia due to defects in GLRX5 Pathogenesis and epidemiology GLRX5 (OMIM 6095588) encodes for the mitochondrial disulfide glutaredoxin (GLRX) 5, which is highly expressed in early erythroid cells and is essential for the biosynthesis of Fe-S clusters ( Figure 1 ). In vitro data show that in GLRX5 deficient erythroblasts, Fe-S cluster production is decreased, and more active Iron Responsive Protein 1 (IRP1) is present in the cytosol. This reflects a low-iron state of the cell and causes repression of target genes, including ALAS2 , resulting in reduced heme synthesis, in mitochondrial iron accumulation, and increased turnover of ferrochelatase. 84,85 Sideroblastic anemia due to defects in GLRX5 is a rare autosomal recessive disease: only one male patient has been described. 86 Clinical presentation and diagnosis The patient born from consanguineous parents, presented at age 44 years with type 2 diabetes mellitus and at 60 years with icterus and hepatosplenomegaly. There was a progressive microcytic anemia with increased TSAT, serum ferritin and iron accumulation in both bone marrow macrophages and erythroblast mitochondria. Treatment Treatment with iron chelation and erythrocyte transfusion resulted in an increase of Hb and a decrease in serum ferritin. Pyridoxine supplementation was not effective. 3E. Erythropoietic ProtoPorphyria due to defects in FECH (EPP) and gain-of-function mutations in ALAS2 (XLDPP) Pathophysiology and epidemiology Erythropoietic ProtoPorphyria comprises two variants, EPP and (X-linked dominant protoporphyria) XLDPP and belongs to the cutaneous porphyrias characterized by accumulation of free protoporphyrin IX. Autosomal recessive EPP (OMIM 177000) is caused by defects in FECH (OMIM 612386), encoding for ferrochelatase in the mitochondrium that is responsible for iron insertion into protoporphyrin IX to form heme ( Figure 1 ). 87 The prevalence differs worldwide, and mode of inheritance is complex.