X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation patterns
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- 作者：Manuel Aivado ; Norbert Gattermann ; Astrid Rong ; Aristoteles A.N. Giagounidis ; Wolf C. Prall ; Akos Czibere ; Barbara Hildebrandt ; Rainer Haas and Sylvia S. Bottomley
- 关键词：X-linked sideroblastic anemia ; Erythroid 5-aminolevulinate synthase ; Skewed X-chromosome inactivation patterns ; Unfortunate skewing
- 刊名：Blood Cells, Molecules, and Diseases
- 出版年：2006
- 出版时间：July-August 2006
- 年：2006
- 卷：37
- 期：1
- 页码：40-45
- 全文大小：159 K
文摘
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.