Albertine Donker

X-linked Sideroblastic Anemia in the Netherlands 215 6 DISCUSSION Our Dutch case series are illustrative for the pathophysiology, the biochemical and clinical presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the (early) diagnosis, follow-up and treatment of this disease. In this article we add a novel mutation to the previously described 61 different ALAS2 mutations reported in 120 families with XLSA. 21-24 All of our 15 XLSA patients had microcytic anemia and all had a mutation in the exon 9 domain of the X-chromosome. In 10 out of 11 families (13 out of 15 patients) it concerned a p.Arg452His mutation, making this the most prevalent mutation in Dutch XLSA patients. Search for a founder effect by haplotype analysis in seven of the families with this mutation suggests that this mutation arose from a common ancestor in six of them. Worldwide the p.Arg452His is also the most frequent ALAS2 defect in XLSA . In one patient a novel p.Cys471Tyr mutation was found. Bio-informatic analysis and family genotype-phenotype association study was highly suggestive for a pathogenic defect. Recently, we reported on a 12 th Dutch Family with XLSA due to a g.55054634G>C mutation in the GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. 24 Age of diagnosis, degree of anemia and iron overload widely differed between these patients, illustrating heterogeneity in the clinical and biochemical penetrance of this congenital disease. One of our patients (patient 3) illustrates that besides anemia, severe systemic iron overload can occur at early age in transfusion independent XLSA patients. Preclinical and clinical studies in ß thalassemia major and intermedia and other iron loading anemias suggest the ineffective erythropoiesis in these disorders may increase the production of humoral factors that may include growth differentiation factor 15 (GDF15), twisted gastrulation (TWSG1) and erythroferrone (ERFE) 25-27 that lead to decreased production of the iron-regulatory hepatic peptide hormone hepcidin (reviewed in 28 ). Hepcidin acts by inhibiting intestinal iron absorption and macrophage recycling of iron from senescent erythrocytes. Suppression of hepcidin production by these proteins has been suggested to cause inappropriately high intestinal iron absorption and iron release from the reticulo-endothelial system (RES), despite iron overload. 25-28