Albertine Donker

X-linked Sideroblastic Anemia in the Netherlands 217 6 Because of the co-existence of normal and affected erythroblasts this anemia may be normocytic with an increased red cell distribution with (RDW) or even two separate erythrocyte populations. 31 Patient 1A also shows that even in elderly patients who present with anemia, a congenital disorder should be considered. Interestingly, Furuyma et al describe a male patient with chronic renal failure who developed sideroblastic anemia at the age of 81 years. This patient was found to have an ALAS2 mutation which only became manifest by an acquired pyridoxine deficiency due to hemodialysis. 32 Anecdotal data support the possibility of misdiagnosing XLSA for MDS-RARS (myelodysplastic syndrome-refractory anemia with ringed sideroblasts) without MDS specific cytogenetic and genetic abnormalities in elderly people. This may be attributed to the fact that the diagnosis of MDS is solely based on the morphological aspect of the bone marrow, which is often difficult. 33 Our patient 9 also was originally diagnosed with MDS (type RCMD) based on the morphologic aspect of bone marrow biopsy, despite low MCH and MCV and a grandfather, who was diagnosed with inherited primary sidero-achrestic anemia 50 years ago. 20 Even in retrospect, however, ring sideroblasts, characteristic for SA, were not seen in the bone marrow. We have no explanation for this phenotype. To the best of our knowledge, no studies are available on the prevalence of inherited ALAS2 mutation among patients diagnosed with MDS with refractory anemia (RARS, RA and RCMD). However, in a recent study among 137 sideroblastic anemias, XLSA patients had MCV levels below the reference range, whereas MCV of patients with MDS-RARS and MDS-RCMD was within reference range. 34 This indicates that a reduced MCV is important to distinguish XLSA from MDS with refractory anemia. As illustrated by our case series, in many patients with XLSA the anemia is to some extent, responsive to pyridoxine. Pyridoxine is metabolized to pyridoxal 5’phosphate, the cofactor for ALAS2. Pyridoxine responsive XLSA is generally based on missense mutations that reduce the affinity between ALAS2 and pyridoxal 5’phosphate, resulting in a shorter half-life of the enzyme. In these cases treatment with high dose of the cofactor pyridoxine partly enhances the stability of ALAS2. 10 ALAS2 mutations that alter the post-translational processing resulting in diminished enzyme activity are mostly pyridoxine unresponsive. 10 Apart from the mutation, the iron status is also important for the pyridoxine responsiveness, because iron overload may compromise mitochondrial function and hence heme biosynthesis. Therefore,