Albertine Donker

Chapter 6 212 Figure 1. Course of hemoglobin and ferritin in patient 2B diagnosed with XLSA and HFE -related hemochromatosis from the onset of phlebotomies A male patient (Table 1, patient 2B) was diagnosed with sideroblastic anemia and HFE -related hemochromatosis at the age of 2 years. At the age of 16 years treatment was started with phlebotomies because of increasing serum ferritin levels. The patient treatment consisted of a 200 mL phlebotomy every 2 weeks during 8 weeks, followed by 400 mL blood drawings every 2 weeks for another 22 weeks. Within a 30-week time frame this treatment resulted in a significant decrease in ferritin levels and an increase in Hb. These data illustrate that reduction of systemic iron overload improves erythropoiesis in XLSA patients. X-axis indicates weeks after start of treatment with phlebotomies; X, Hb concentration; ▲, serum ferritin level. Molecular features Thirteen out of the 15 patients showed hemizygosity for the previously reported pathogenic c.1355G>A (p.Arg452His) mutation in exon 9 of the ALAS2 gene. One female patient was heterozygous for the c.1355G>A (p.Arg452His) mutation (patient 1A). These 13 patients with a p.Arg452His mutation, are from 10 apparently unrelated families. Haplotype analysis of patients 3 and 6-11 showed that all patients, except for proband 9, carried the same length of the 4 STR’s analyzed, suggesting that the p.Arg452His mutation arose from one common ancestor in these probands. The lengths of all 4 STR’s of the patients differed from those found for proband 9. The common haplotype of patients 3, 6-8, 10 and 11 is at least 2.473 kilobase in size. In two patients (brothers 5A and 5B) a novel mutation was found in exon 9: c.1412G>A (p.Cys471Tyr). For this mutation bio-informatic tools were not consistent in their assessment, i.e. SIFT predicted the mutation as non-pathogenic, whereas PolyPhen predicted the mutation as “probably damaging”. HOPE reports: “the wild type