LATE-ONSET X-LINKED SIDEROBLASTIC ANEMIA

X-linked sideroblastic anemia (XLSA) is caused by mutations of the ery throid-specific delta-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis. The characteristic hypochromic, microcyti c anemia typically becomes manifest in the first three decades of life . Hematologic response to pyridoxine is variable and rarely complete. We report two unrelated cases of highly pyridoxine-responsive XLSA in geriatric patients previously diagnosed with refractory anemia and rin ged sideroblasts. A previously unaffected 77-yr-old male and an 81-yr- old female were each found to have developed severe hypochromic, micro cytic anemia with ringed sideroblasts in the bone marrow, which respon ded dramatically to pyridoxine with normalization of hemoglobin values . Sequence analysis identified an A to C transversion in exon 7 (K299Q ) of the ALAS2 gene in the male proband and his daughter. In the femal e proband a G to A transition was identified in exon 5 (A172T). This m utation resulted in decreased in vitro stability of bone marrow delta- aminolevulinate synthase activity. Each patient's recombinant mutant A LAS2 enzyme had marked thermolability, Addition of pyridoxal 5'-phosph ate in vitro stabilized the mutant enzymes, consistent with the observ ed dramatic response to pyridoxine in vivo. This late-onset form of XL SA can be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and ALAS2 mutations. Thes e findings emphasize the need to consider all elderly patients with mi crocytic sideroblastic anemia as candidates for XLSA, especially if py ridoxine responsiveness is demonstrated.