Albertine Donker

Chapter 1 30 Microcytic anemia not explained by acquired iron deficiency or thalassemia might indicate a genetic disorder of iron metabolism or heme synthesis Microcytic anemias are primarily caused by ID as a consequece of nutritional deficits, gastro-intestinal or gynecological blood loss or iron malabsorption. 1-3 In specific populations, hemoglobinopathies, espcially thalassemia syndromes are also a common cause of microcytic anemias. 1 However, not all cases of microcytic anemias can be explained by acquired ID or hemoglobinopathy. Assessment of serum iron parameters is paramount in these patients; abnormal transferrin saturation (TSAT) and/or increased ferritin levels might indicate a genetic disorder of iron metabolism or heme synthesis. Especially in case of a positive family history for anemia and/ or iron loading, early onset of anemia or anemia that is refractory or incompletely responsive to iron supplementation, clinicians should be aware of a possible genetic cause of microcytic anemia. Additional features as neurologic disease and skin photosensitivity may also be suggestive of these disorders. Several defects in genes with roles in systemic and cellular iron metabolism and heme synthesis have been identified as being involved in the pathogenesis of genetic microcytic anemias. 6-9 Pathogenic variants of these genes may result in low iron availability for erythropoiesis, impaired iron acquisition by the erythroid precursors, or defects in heme and/or Fe/S cluster synthesis. In this thesis we focus on these disorders with the emphasis on Iron Refractory Iron Deficiency Anemia (IRIDA) due to TMPRSS6 defects, a disorder of low iron availability for erythropoiesis, and on X-linked Sideroblastic anemia (XLSA) due to ALAS2 defects resulting in impaired heme synthesis. Iron Refractory Iron Deficiency Anemia: a clinically and genetically a heterogeneous disease MT2, encoded by TMPRSS6, plays an essential role in providing adequate iron supply to the erythroblasts by down-regulating hepcidin ( Figure 2 ). Pathogenic TMPRSS6 defects result in uninhibited hepcidin production despite low body iron levels, causing IRIDA, a disease characterized by a microcytic, hypochromic anemia due to serum hepcidin values that are inappropriately high for circulating iron levels ( Figure 5 ). 22,34,37,107-109