Albertine Donker

Chapter 3 108 genetic form of sideroblastic anaemia. 3 Since Cooley described the first patients with XSLA in 1945, 74 61 different pathogenic ALAS2 defects have been described in 120 non-related families. 75,76 As in most X-linked disorders, most female carriers of XLSA are asymptomatic. However, women with ALAS2 mutations may be affected due to skewed X–inactivation. 77 Furthermore, physiologic age-related skewed X –inactivation in hematopoietic stem cells may play a role in developing XLSA in female carriers with increasing age. 78 Estimates on the prevalence of ALAS2 defects are not available. Since the phenotype might be mild, under- diagnosis is likely. Clinical presentation and diagnosis XLSA is characterized by mild hypochromic, microcytic, sideroblastic anemia in combination with systemic iron overload. 3 Elevated Red cell Distribution Width (RDW) has been described in female carriers of the mutation and is ascribed to the presence of two erythrocyte populations. 79 Phenotypic expression of XLSA is highly variable even in patients with identical mutations. 80 Case reports indicate that affected males generally present in the first two decades of life with symptoms of anemia or later with either manifestations of anemia or those of parenchymal iron overload. Manifestation at elderly age due to an acquired pyridoxine deficiency is described. 81 Treatment The available evidence indicates that initial doses of oral vitamin B6 (pyridoxine) 50- 200 mg/day are effective in improving anemia and iron overload in all responsive XLSA patients. 82 Occasionally high doses may be considered. Once a response is obtained evidence suggests the life-long maintenance dose may be lowered to 10- 100 mg/day, since too high doses may give neurotoxicity. 83 Since iron overload may compromise mitochondrial function and hence heme biosynthesis, XLSA patients should not be considered pyridoxine refractory until iron stores are normalized. 73 Most patients can be treated with phlebotomies for iron overload, since the anemia is mild. Hb typically increases, rather than decreases, after reversal of iron overload by phlebotomies. 73