Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females

X-linked sideroblastic anemia (XLSA) is caused by mutations in the erythroi d-specific 5-aminolevulinic acid synthase (ALAS2) gene. An elderly woman wh o presented with an acquired sideroblastic anemia is studied. Molecular ana lysis revealed that she was heterozygous for a missense mutation in the ALA S2 gene, but she expressed only the mutated gene in reticulocytes. Her 2 da ughters and a granddaughter were heterozygous for this mutation, had normal hemoglobin levels, and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia both in the proband and her grandson. All women who we re analyzed in this family showed skewed X-chromosome inactivation in leuko cytes, which indicated a hereditary condition associated with unbalanced ly onization. Because the preferentially active X chromosome carried the mutan t ALAS2 allele, acquired skewing in the elderly likely worsened the genetic condition and abolished the normal ALAS2 allele expression in the proband. (Blood, 2000;96:4363-4365) (C) 2000 by The American Society of Hematology.