LATE-ONSET X-LINKED SIDEROBLASTIC ANEMIA
LATE-ONSET X-LINKED SIDEROBLASTIC ANEMIA
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DOI：
10.1172/jci118258
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发表时间：
1995-10-01
影响因子：
15.9
通讯作者：
BISHOP, DF
中科院分区：
文献类型：
--
作者：
COTTER, PD;MAY, A;BISHOP, DF
X-连锁铁粒幼细胞性贫血（XLSA）是由红细胞特异性δ-氨基乙酰丙酸合酶基因（ALAS 2）突变导致血红素合成不足引起的。典型的低色素、小红细胞性贫血通常在生命的前三十年变得明显。血液学反应吡哆醇是可变的，很少完全。我们报告两个不相关的情况下，高度吡哆醇反应XLSA老年患者先前诊断为难治性贫血和环形铁粒幼细胞。一名之前未受影响的77岁男性和一名81岁女性均被发现患有严重的低色素、小细胞性贫血，骨髓中存在环形铁粒幼细胞，这对维生素B6有显着反应，血红蛋白值恢复正常。序列分析证实先证者及其女儿的ALAS 2基因第7外显子（K299 Q）存在A到C的颠换。在女性先证者中，在外显子5（A172 T）中确定了G到A的转换。该突变导致骨髓δ-氨基乙酰丙酸合酶活性的体外稳定性降低。每个患者的重组突变ALAS 2酶具有显著的热不稳定性。在体外添加吡哆醛5 '-磷酸稳定了突变酶，与体内观察到的对吡哆醇的显著反应一致。这种迟发性XLSA可通过小红细胞增多、吡哆醇反应性和ALAS 2突变与难治性贫血和环形铁粒幼细胞区分。这些发现强调需要考虑所有小红细胞铁粒幼细胞性贫血的老年患者作为XLSA的候选人，特别是如果吡哆醇反应性得到证明。
X-linked sideroblastic anemia (XLSA) is caused by mutations of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis. The characteristic hypochromic, microcytic anemia typically becomes manifest in the first three decades of life. Hematologic response to pyridoxine is variable and rarely complete. We report two unrelated cases of highly pyridoxine-responsive XLSA in geriatric patients previously diagnosed with refractory anemia and ringed sideroblasts. A previously unaffected 77-yr-old male and an 81-yr-old female were each 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 male proband and his daughter. In the female proband a G to A transition was identified in exon 5 (A172T). This mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. Each patient's recombinant mutant ALAS2 enzyme had marked thermolability, Addition of pyridoxal 5'-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of XLSA can be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and ALAS2 mutations. These findings emphasize the need to consider all elderly patients with microcytic sideroblastic anemia as candidates for XLSA, especially if pyridoxine responsiveness is demonstrated.