Albertine Donker

Chapter 6 216 We previously reported that patient 2A indeed had elevated serum GDF15 levels that were associated with inappropriately low serum hepcidin in relation to his iron stores, as reflected by a low hepcidin/ferritin ratio. 18 We did not measure serum GDF15 and/ or serum hepcidin in our other SA patients since the results have no therapeutic implications. As far as we know, no studies are available on the above-mentioned humoral factors or hepcidin in SA patients due to ALAS2 defects. In general, systemic iron overload develops in the third or fourth decade, also in patients without overt anemia. 1,2 This emphasizes the importance of early diagnosis, since the effects of systemic iron overload are potentially very serious, such as liver cirrhosis and HCC, especially in the presence of concurrent liver toxic conditions (alcohol abusus or non-alcoholic steato-hepatitis). Moreover, we suggest that first- degree relatives should be screened for the relevant mutation, because they may develop severe iron overload without any signs and symptoms of anemia. This phenotype of iron overload with only mild anemia may lead to a false diagnosis of hereditary hemochromatosis. We suggest that ALAS2 mutations might be the underlying cause of patients (falsely) diagnosed with unexplained forms of HH. In these cases, the low MCV should point the clinician to the presence of an iron- loading anemia such as XLSA. To the best of our knowledge the prevalence of ALAS2 defects among patients with genetically unexplained HH is unknown. Other genes implicated in iron metabolism and HH may also affect the phenotype of XLSA. Anecdotal data support the suggestion that coinheritance of heterozygosity of the p.Cys282Tyr mutation in the HFE gene is likely increased in XLSA patients with moderate to severe phenotypes. 11,29,30 It is well possible that penetrance of HH due to homozygosity for the p.Cys282Tyr mutation might be modified by ALAS2 mutations and vice versa, as the biochemical presentation of patient 2B suggests, i.e. he developed systemic iron overload already in his teens. The majority of female carriers of XLSA are asymptomatic, as in most X-linked recessive disorders. However, as illustrated by patient 1A, they may be affected due to the predominant inactivation of the normal X-chromosome. Furthermore, physiologic age-related skewed X –inactivation in hematopoietic cells may play a role in developing XLSA in female carriers with increasing age. So a combination of congenital and acquired skewing can result in late onset of XLSA in women. 6-8