Albertine Donker

Summary 339 10 In Chapter 5 we commented on a case report of a suggested IRIDA case of a 10-years old Chinese girl, at the age of 10 months diagnosed with a splenomegaly and a severe microcytic anemia (Hb 5.8 g/dL, MCV 61 fL), with a decreased TSAT of 7%. The child was neither responding to oral iron nor to a combination of intravenous iron and erythropoietin. IRIDA was diagnosed in this child because of increased hepcidin levels (12.0 nmol/L) compared to the normal ranges for females for this specific hepcidin assay (4.0 ± 1.5 nmol/L) and because of the non-synonymous TMPRSS6 changes c.757A>G (p.Lys253Glu, K253E, rs2235324) and c.2207 T>C (p.Val736Ala, V736A, rs855791). Because of the refractoriness to oral iron, parenteral iron and erythropoietin, a steroid trial was performed. Strikingly, hepcidin levels dropped to 2.7 nmol/L and Hb increased to 8.9 g/dL on this treatment. We argued that the clinical course was more consistent with anemia of inflammation than with IRIDA because of the sharp decline of serum hepcidin levels after the initiation of the anti-inflammatory drug methylprednisolone and because of the occurrence of splenomegaly that is not typical of IRIDA. We debated the pathogenicity of the above- mentioned TMPRSS6 variants that are common non-synonymous polymorphisms, also for the Han Chinese population, and therefore unlikely to be the cause of IRIDA with such a severe microcytic anemia. Moreover, we discussed the functional studies indicating that the TMPRSS6 736A variant inhibits hepcidin more efficiently than 736V variant, implicating that the presence of the 736A variant in the patient protects against instead of causes elevated hepcidin levels and iron deficiency. In Chapter 6 we presented clinical and genetic data of 15 Dutch patients from 11 unrelated families diagnosed with XLSA patients, which is the most common inherited form of sideroblastic anemia, characterized by mostly mild hypochromic microcytic anemia with bone marrow ring sideroblasts, in combination with mild to severe parenchymal iron loading due to ineffective erythropoiesis. The disease is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene ( ALAS2 ). We reviewed age of presentation, clinical and biochemical features, ALAS-2 defects and treatment characteristics (e.g. pyridoxine, blood transfusion, chelation, phlebotomy) of the patients. Although 10 out of 11 families shared the same previously described c.1355G>A (p.Arg452His) ALAS2 defect, phenotype regarding severity of anemia and iron loading was very different, even for those six patients with the p.Arg452His defect in which haplotype analysis strongly suggested ancestral