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首页> 美国卫生研究院文献>American Journal of Human Genetics >Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease
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Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease

机译：由于纯合DHFR突变导致二氢叶酸还原酶缺乏症导致巨幼细胞性贫血和脑叶酸缺乏症导致严重的神经系统疾病

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The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate.
机译：细胞内叶酸代谢的重要性可以通过先天性叶酸代谢紊乱或叶酸缺乏引起的症状和并发症的严重性来说明。我们检查了三名健康，远亲父母的孩子，这些孩子表现出巨幼细胞性贫血和脑叶酸缺乏症，导致神经系统疾病并伴有非典型的儿童期癫痫发作。全基因组的纯合性作图揭示了5号染色体上的候选区域，包括二氢叶酸还原酶（DHFR）基因座。 DHFR测序显示在所有兄弟姐妹中均存在纯合的DHFR突变，c.458A> T（p.Asp153Val）。通过液相色谱串联质谱分析，患者在红细胞（RBC），血浆和脑脊液（CSF）中的叶酸谱与DHFR缺乏症相符。在所有患者的EBV永生化淋巴母细胞中，DHFR活性和荧光素标记的甲氨蝶呤（FMTX）结合严重降低。杂合细胞表现出中等的DHFR活性和FMTX结合。 DHFR mRNA的RT-PCR显示野生型和DHFR突变携带细胞之间没有差异，而具有DHFR突变的细胞中蛋白质表达降低。亚叶酸治疗可解决血液学异常，脑脊液叶酸水平正常化和神经系统症状改善。总之，纯合子DHFR突变p.Asp153Val导致DHFR缺乏，并导致可以用亚叶酸成功治疗的复杂血液和神经疾病。 DHFR对于维持足够的CSF和RBC叶酸水平是必要的，即使在营养叶酸供应充足且血浆叶酸正常的情况下也是如此。

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