Albertine Donker

X-linked Sideroblastic Anemia in the Netherlands 205 6 INTRODUCTION X-linked sideroblastic anemia (XLSA; OMIM #300751) is the most common inherited form of sideroblastic anemia (SA) and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene ( ALAS2 ), which is the first and rate limiting step of heme-biosynthesis. 1-3 The disorder is characterized by hypochromic microcytic anemia with ring sideroblasts in the bone marrow in combination with systemic iron overload due to ineffective erythropoiesis. 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 iron overload. Occasionally patients present later in life. 4,5 As in most X-linked recessive disorders, the majority of female carriers of XLSA are spared from clinical manifestations. However, 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. 6-8 Standard treatment of XLSA consists of high dose pyridoxine supplementation and iron reducing strategies like phlebotomies and iron chelation. 9 The effect of high dose pyridoxine 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. 10 Reduction of iron overload in XLSA improves erythropoiesis and prevents complications of chronic iron overload, especially liver cirrhosis and hepatocellular carcinoma. 11-13 In this article we describe 14 male patients and one female patient from 11 unrelated families. All patients are from Dutch origin. These case series are illustrative for 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 the disease.