Albertine Donker

Chapter 1 34 enhancer element in the intron of ALAS2, that contains a GATA-binding site, results in clinical phenotypes of XLSA. 134 The disorder is characterized by hypochromic microcytic anemia with ring sideroblasts in erythroid precursor cells in the bone marrow in combination with systemic IO. The IO in XLSA, which is predominantly of parenchymal nature, is thought to be a result of inappropriately low hepcidin levels as a consequence of elevated ERFE levels due to ineffective erythropoiesis, as seen other iron loading anemias, like β-thalassemias, and also occurs in un-transfused patients. 98,99 However, no data on serum hepcidin levels or ERFE levels in XLSA patients are available. Phenotypic expression of XLSA is highly variable even in patients with identical mutations, but affected males generally present in the first decades of life with symptoms of anemia or later with manifestations of parenchymal IO. As in most X-linked recessive disorders, the majority of female carriers of XLSA are spared from clinical manifestations. Sporadically women with ALAS2 mutations may be affected due to inactivation of the normal X-chromosome or age-related skewed X-inactivation in hematopoietic cells. 135-137 Recently a family has been described with multiple females affected by macrocytic anemia whereby whole exome sequencing (WES) revealed an ALAS2 defect. In the reticulocytes of the affected females a complete skewing towards expression of the wildtype allele was found, in contrast to the above-mentioned possible unfavorable lionization pattern with skewing towards expression of the mutated allele causing a phenotype of XLSA with microcytic anemia and IO. The results of the X inactivation pattern studies in this family illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis. 138 Standard treatment of XLSA consists of high dose pyridoxine supplementation and iron reducing strategies like phlebotomies and iron chelation. 10 The effect of high dose vitamin B6 is based on the high prevalence of mutations in the pyridoxine- binding region of the ALAS2 -gene. The high dose enhances the half-life of ALAS2, however, this is not true for mutations outside this region. 139 Reduction of IO in XLSA improves erythropoiesis and prevents complications of chronic parenchymal iron overload, especially liver cirrhosis and hepatocellular carcinoma. 99,140 A timely diagnosis of XLSA therefore avoids unnecessary investigations for other causes of microcytic anemia and allows early detection of subclinical, progressive IO that may result in severe morbidity of even mortality if it goes unnoticed.