title: X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation patterns.
abstract: Historically X-linked sideroblastic anemia, with rare exceptions, was thought to be manifested only in males. Since the discovery of the erythroid-specific isoform of 5-aminolevulinate synthase (ALAS2) and the cloning of its gene (ALAS2) 15 years ago, mutation analysis has revealed that clinical expression of this X-linked disorder is prevalent in females as well. However, presence of the disease in both genders within affected kindreds appears to be very uncommon. We report a unique family with the disorder in three women who have had widely disparate clinical courses. The anemia is associated with a previously unrecognized ALAS2 mutation (Arg436Trp) and is unresponsive to pyridoxine. To clarify the varied clinical courses of the patients, X-chromosome inactivation patterns were examined in hematopoietic and non-hematopoietic cells. We observed inactivation patterns supporting the conclusions that one daughter has a mild phenotype at age 31 because of moderate constitutive skewed X-chromosome inactivation, another daughter with clinical onset at age 16 is severely affected due to extreme constitutive X-skewing, whereas the mother developed progressive anemia in the fifth decade as she acquired an age-related non-random X-inactivation in hematopoietic cells. In addition, we observed random X-inactivation in reticulocytes of all three women that contrasted with a markedly skewed inactivation pattern in bone marrow erythroid cells. This discordance is attributable to apoptosis of erythroid precursors derived from progenitor cells with an active X-chromosome bearing the ALAS2 mutation. The features of the disorder in this family are also instructive in regard to the differential diagnosis of sideroblastic anemias in women.
authors.affiliation: Department of Hematology, Oncology, and Clinical Immunology, Heinrich Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. maivado@bidmc.harvard.edu
authors.forename: Manuel
authors.initials: M
authors.lastname: Aivado
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
authors.forename: Astrid
authors.initials: A
authors.lastname: Rong
authors.forename: Aristoteles A N
authors.initials: AA
authors.lastname: Giagounidis
authors.forename: Wolf C
authors.initials: WC
authors.lastname: Prall
authors.forename: Akos
authors.initials: A
authors.lastname: Czibere
authors.forename: Barbara
authors.initials: B
authors.lastname: Hildebrandt
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Bottomley
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000756:Anemia, Sideroblastic / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D015672:Erythroid Precursor Cells; D005192:Family Health; D005260:Female; D040181:Genetic Diseases, X-Linked; D006801:Humans; D040582:Inheritance Patterns; D009154:Mutation; D049951:X Chromosome Inactivation
chemical_list: D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human