Albertine Donker

Rare Inherited Iron and Heme-related Anemias 95 3 The majority of the articles retrieved were case reports or small case series. The searches also showed a number of reviews, however, none of them used a systematic approach. Therefore, we modified the usual therapeutic/intervention-based system for grading the evidence 9,10 of the conclusions in supplement 2 in the following levels: 1. Proven or very likely based on results by numerous investigators, in various populations and settings, 2. Probable based on moderate number of reports 3. Indicative based on small number of reports 4. Expert opinion of members of the working group. Working group The working group consisted of the authors of this article. Definitions This guideline covers microcytic anemias due to genetic defects in iron metabolism or heme synthesis ( Table 2 ). For the selection of these diseases, we used recent reviews, 1,4 and added disorders that were described in more recent years, i.e. sideroblastic anemia due to defects in STEAP3 and X-linked dominant protoporphyria (XLDPP). We excluded microcytic anemia caused by hemoglobinopathies and genetic diseases not predominantly characterized by a primary defect in iron metabolism or heme synthesis ( Figure 2 and its legend). Introduction in iron metabolism and heme synthesis Iron plays an essential role in many biochemical processes, in particular in the production of heme for the incorporation in hemoglobin and myoglobin, and iron- sulphur clusters, which serve as enzyme cofactors. 11 In case of iron deficiency, cells lose their capacity for electron transport and energy metabolism. Clinically, iron deficiency causes anemia and may result in neurodevelopmental deficits. 12 On the other hand, iron excess leads to complications such as endocrine disorders, liver cirrhosis and cardiac dysfunction. 13 Therefore, tight regulation of body iron homeostasis on systemic and cellular level is paramount. These processes comprise several proteins, most of which have been discovered in the last 20 years. Defects in these proteins lead to disorders of iron metabolism and heme synthesis that are characterized by iron overload, iron deficiency or iron maldistribution.