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

• Published in: Blood Vol. 96; no. 13; pp. 4363 - 4365
• Main Authors: Cazzola, Mario, May, Alison, Bergamaschi, Gaetano, Cerani, Paola, Rosti, Vittorio, Bishop, David F.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-12-2000; The Americain Society of Hematology
• Subjects: 5-Aminolevulinate Synthetase - deficiency; 5-Aminolevulinate Synthetase - genetics; Adolescent; Adult; Aged; Alleles; Anemia, Refractory - diagnosis; Anemia, Sideroblastic - diagnosis; Anemia, Sideroblastic - drug therapy; Anemia, Sideroblastic - enzymology; Anemia, Sideroblastic - genetics; Anemias. Hemoglobinopathies; Biological and medical sciences; Blood Transfusion; Diagnosis, Differential; Diagnostic Errors; Diseases of red blood cells; Dosage Compensation, Genetic; Female; Hematologic and hematopoietic diseases; Hematopoiesis; Heterozygote; Humans; Leukocytes - enzymology; Male; Medical sciences; Middle Aged; Pedigree; Pyridoxine - therapeutic use; Thalassemia - diagnosis; X Chromosome - genetics; Human; Acyltransferases; Sex linked character; Late; Enzyme; Transferases; Clinical form; Hemopathy; Sideroblastic anemia; 5-Aminolevulinate synthase; Inactivation; Myelodysplastic syndrome; Case study; EC 2.3.1.37; Gene; Risk factor; Genetics; Female; Reticulocyte; X-Chromosome; Mutation; Elderly
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V96.13.4363

X-linked sideroblastic anemia (XLSA) is caused by mutations in the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) gene. An elderly woman who presented with an acquired sideroblastic anemia is studied. Molecular analysis revealed that she was heterozygous for a missense mutation in the ALAS2 gene, but she expressed only the mutated gene in reticulocytes. Her 2 daughters 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 were analyzed in this family showed skewed X-chromosome inactivation in leukocytes, which indicated a hereditary condition associated with unbalanced lyonization. Because the preferentially active X chromosome carried the mutant ALAS2 allele, acquired skewing in the elderly likely worsened the genetic condition and abolished the normal ALAS2 allele expression in the proband.