Albertine Donker

Rare Inherited Iron and Heme-related Anemias 107 3 complexes ( Figure 1 ). 3,68 Defects in ABCB7 result in disrupted iron metabolism and heme synthesis causing a mild, slightly microcytic, sideroblastic anemia but also cerebellar ataxia. 69 Sideroblastic anemia with ataxia due to defects in ABCB7 is a rare, X-linked disease. 69 Seventeen patients with four different pathogenic ABCB7 defects have been described in case reports, of which five were female, which might be explained by skewed X-inactivation. None of the women showed neurological defects. There is no apparent genotype-phenotype correlation. Clinical presentation and diagnosis The presenting symptom in all male patients was cerebellar ataxia that developed in childhood. Cerebral MRI showed cerebellar hypoplasia in four patients. Mild, slightly microcytic, sideroblastic anemia was found, usually in the second decade. In 10 patients free erythrocyte protoporphyrin IX was increased. None of the patients showed systemic iron loading. Treatment Treatment of the mild anemia is not reported. 3C. X- linked sideroblastic anemia due to defects in ALAS2 Pathophysiology and epidemiology ALAS2 (OMIM 301300) is located on chromosome X and encodes for ALAS2, an erythroid specific isoform of the catalytic enzyme involved in heme synthesis in the mitochondria ( Figure 1 ). 70 Almost all ALAS2 defects are missense mutations, most commonly in domains important for catalysis or pyridoxal phosphate (vitamin B6) co-factor binding . 71 Recently also defects in the binding site of the transcription factor GATA1 in the first intron of ALAS2 have been described. 72 ALAS2 defects result in decreased protoporphyrin synthesis and subsequent reduced iron incorporation and heme synthesis, causing microcytic anemia and erythroid mitochondrial iron loading. Mitochondrial iron loading exacerbates the anemia through decreased pyridoxine sensitivity. 73 Heme deficiency is associated with ineffective erythropoiesis, followed by increased intestinal iron uptake and tissue iron accumulation. X-linked sideroblastic anemia (XLSA) is the most common