Initially Diagnosed with Acquired Refractory Anemia and Ringed Sideroblasts

X-linked sideroblastic anemia (XLSA) is caused by mutations of the erythroid-specific 6-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis. The characteristic hypochromic, microcytic 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 ringed sideroblasts. A previously unaffected 77-yr-old male and an 81-yr-old female were each found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded 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 female proband a G to A transition was identified in exon 5 (A172T). This mutation resulted in decreased in vitro stability of bone marrow 6-aminolevulinate synthase activity. Each patient's recombinant mutant ALAS2 enzyme had marked thermolability. Addition of pyridoxal 5 '-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of XLSA can be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and ALAS2 mutations. These findings emphasize the need to consider all elderly patients with microcytic sideroblastic anemia as candidates for XLSA, especially if pyridoxine Portions of this work were presented at the 42nd Meeting of the American Society of Human Genetics in San Francisco, CA from 9 to 13 November 1992, and the First Meeting of the European Haematology Association in Brussels, Belgium from 3 to 5 June 1994. Address correspondence to D. F. Bishop, Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029. Phone: 212-241-6946; FAX; 212-360-1809; E-mail, bishop@msvax. mssm.edu. Received for publication 13 April 1995 and accepted in revised form 22 June 1995. responsiveness is demonstrated. (J. Clin. Invest. 1995. 96:2090-2096.)