Cotter et al. (1995) reported 2 unrelated cases of X-linked sideroblastic anemia-1 (SIDBA1; 300751) that were atypical in 2 respects: unlike the usual form which is manifest in the first 3 decades of life and in which the hematologic response to pyridoxine is variable and rarely complete, the 2 patients were highly pyridoxine-responsive and were in the geriatric age group. A previously unaffected 77-year-old male and an 81-year-old female, who were previously well, were 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 man as well as his daughter, while the female proband showed a G-to-A transition in exon 5 (A172T; 301300.0006). The latter mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. The recombinant mutant ALAS2 enzyme of each patient had marked thermal lability. Addition of pyridoxal 5-prime-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of X-linked sideroblastic anemia could be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and, of course, ALAS2 mutations. Cotter et al. (1995) suggested that all patients with acquired sideroblastic anemia should be tested for pyridoxine responsiveness. Relatively modest deficiencies of folate or vitamin B12 may explain late-onset anemia in patients with previously compensated hemolytic states due to inherited cytoskeletal defects, e.g., hereditary spherocytosis, or glycolytic pathway enzyme deficiencies, e.g., pyruvate kinase deficiency. The authors stated that age-associated nutritional deficiencies due to subtle alterations in vitamin B6 availability or metabolism may unmask an inherited disorder when a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate.
By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of lys299 by glutamine causes decreased binding affinity of ALAS for sCoA. Patients with this mutation have been reported to respond to pyridoxine treatment; however, as PLP binding in ALAS is not affected by the mutation, the effect of pyridoxine supplementation may be indirect.
