Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders.
Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders.
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DOI：
10.1371/journal.pone.0008318
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发表时间：
2009-12-15
期刊：
影响因子：
3.7
通讯作者：
Fogli A
中科院分区：
文献类型：
--
作者：
Horzinski L;Huyghe A;Cardoso MC;Gonthier C;Ouchchane L;Schiffmann R;Blanc P;Boespflug-Tanguy O;Fogli A
近年来，与真核起始因子2B基因突变相关的脑白质营养不良的表型已被扩展，经典地称为CACH/VWM（儿童共济失调伴中央脊髓灰质炎/白色物质消失障碍）。从导致胎儿死亡的更严重的产前形式到16岁后发病的更温和的成人形式并限于缓慢的认知障碍，观察到的大的临床谱导致了eIF 2B相关疾病的概念。脑白色物质弥漫性CSF样表现的典型MRI模式在成人中尤其缺乏，而越来越多的患者符合CACH/VWM疾病的临床和MRI标准，但没有eIF 2B突变。eIF 2B相关疾病的生化诊断是困难的，因为除了最近描述的在脑脊液中测量的无唾液酸转铁蛋白/转铁蛋白比率之外，迄今为止还没有提出和验证的标志物。先前在30例eIF 2B突变患者的淋巴母细胞系中报告了eIF 2B GEF活性降低。我们的目的是进一步评估该标记物的效用，并在更大的队列中验证eIF 2B GEF活性作为eIF 2B相关疾病的特异性诊断试验。我们在来自63名表现出不同临床形式和eIF 2B突变的患者的细胞中进行了eIF 2B GEF活性测定，与对照组相比，也与没有eIF 2B突变的明确脑白质营养不良或CACH/VWM样疾病的患者进行了比较。我们发现，当活性阈值设定为≤ 77.5%时，eIF 2B突变患者细胞中的GEF活性显著降低，特异性为100%，灵敏度为89%。这些结果验证了患者转化淋巴细胞中eIF 2B GEF活性的测量作为诊断eIF 2B相关疾病的重要工具。
In recent years, the phenotypes of leukodystrophies linked to mutations in the eukaryotic initiation factor 2B genes have been extended, classically called CACH/VWM (Childhood ataxia with cntral hypomyélination/vanishing white matter disorder). The large clinical spectrum observed from the more severe antenatal forms responsible for fetal death to milder adult forms with an onset after 16 years old and restricted to slow cognitive impairment have lead to the concept of eIF2B-related disorders. The typical MRI pattern with a diffuse CSF-like aspect of the cerebral white matter can lack particularly in the adult forms whereas an increasing number of patients with clinical and MRI criteria for CACH/VWM disease but without eIF2B mutations are found. Then we propose the use of biochemical markers to help in this difficult diagnosis. The biochemical diagnosis of eIF2B-related disorder is difficult as no marker, except the recently described asialotransferrin/transferrin ratio measured in cerebrospinal fluid, has been proposed and validated until now. Decreased eIF2B GEF activity has been previously reported in lymphoblastoid cell lines from 30 eIF2B-mutated patients. Our objective was to evaluate further the utility of this marker and to validate eIF2B GEF activity in a larger cohort as a specific diagnostic test for eIF2B-related disorders. We performed eIF2B GEF activity assays in cells from 63 patients presenting with different clinical forms and eIF2B mutations in comparison to controls but also to patients with defined leukodystrophies or CACH/VWM-like diseases without eIF2B mutations. We found a significant decrease of GEF activity in cells from eIF2B-mutated patients with 100% specificity and 89% sensitivity when the activity threshold was set at ≤77.5%. These results validate the measurement of eIF2B GEF activity in patients' transformed-lymphocytes as an important tool for the diagnosis of eIF2B-related disorders.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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