Albertine Donker

Chapter 6 204 ABSTRACT Background: X-linked sideroblastic anemia (XLSA) is the most common inherited form of sideroblastic anemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene ( ALAS2 ). The disorder is characterized by mostly mild hypochromic microcytic anemia with bone marrow ring sideroblasts. Even un-transfused patients with mild or no anemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS2 mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. Methods: We reviewed age of presentation, clinical and biochemical features, ALAS- 2 defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. Results and Conclusions: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and/or (mild) microcytic anemia, also at older age. Key words ALAS2, iron, sideroblastic anemia