综述与专论: 白质消融性白质脑病研究进展
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北京大学第一医院儿科,北京 100034

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国家自然科学基金(82171694)和北京市自然科学基金-海淀原始创新联合基金(L202034)资助项目


Reviews and Monographs: Research Progress of Leukoencephalopathy With Vanishing White Matter
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Department of Pediatrics, Peking University First Hospital, Beijing 100034, China

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This work was supported by grants from The National Natural Science Foundation of China (82171694) and Beijing Natural Science Foundation -Haidian Original Innovation Joint Fund (L202034).

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    摘要:

    白质消融性白质脑病(leukoencephalopathy with vanishing white matter,VWM)是一种常染色体隐性遗传性脑白质病,其致病基因EIF2B 1~5分别编码真核细胞蛋白质翻译起始因子2B(eukaryotic initiation factor 2B,eIF2B)的5个亚基α~ε,其中任一编码基因突变均可引起发病。起病多见于婴幼儿及儿童期,临床表型差异大,典型表现为进行性运动功能退行,可伴共济失调和癫痫。应激(发热、外伤等)可导致发作性加重。影像学显示大脑白质进行性液化。尸解神经病理学特征主要表现为广泛性白质稀疏和囊性变性,无神经胶质细胞反应性增生,星形胶质细胞形态异常,过表达祖细胞标志物巢蛋白(Nestin)和胶质纤维酸性蛋白δ(GFAPδ),少突前体细胞数量增加和成熟少突胶质细胞减少、泡沫化且凋亡增加。VWM致病基因EIF2B 1~5是管家基因,但多数患者通常仅脑白质受累。少数胎儿期及婴儿早期发病的患者可出现多系统受累,成年女性患者可有卵巢功能障碍。目前认为,星形胶质细胞在其致病机制中起着核心作用,病理性星形胶质细胞继发性引起少突胶质细胞成熟障碍和髓鞘形成异常,进而导致脑白质病变。其他疾病机制包括内质网应激后未折叠蛋白反应(UPR)过度激活、线粒体功能障碍、自噬抑制等,尚不完全明确。

    Abstract:

    Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy caused by any of EIF2B 1-5 mutations, encoding five subunits α-ε of eukaryotic translation initiation factor 2B (eIF2B). The clinical phenotype of the disease varies greatly. The typical manifestation is progressive motor function regression, which can be accompanied by ataxia and epilepsy and susceptible to episodic aggravation of stress such as fever and trauma. Imaging showed progressive liquefaction of cerebral white matter. Autopsy neuropathology is characterized by extensive white matter sparseness and cystic degeneration, no reactive proliferation of glial cells, abnormal astrocyte morphology, overexpression of progenitor cell markers Nestin and GFAPδ, and increased number of oligodendrocyte precursor cells and decreased mature oligodendrocytes, foamed and increased apoptosis. The VWM gene EIF2B 1-5 is housekeeping gene, but most patients usually only have white matter involvement. A small number of fetal and early infantile patients may have multisystem involvement, and adult female patients may have ovarian dysfunction. It is currently believed that astrocytes play a central role in the pathogenesis of VWM. Pathological astrocytes cause secondary oligodendrocyte maturation disorder and abnormal myelination, which in turn lead to white matter lesions. Other disease mechanisms, including excessive activation of the unfolded protein response (UPR) after endoplasmic reticulum stress, mitochondrial dysfunction, and autophagy inhibition, are not fully understood.

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邓泂,吴晔.综述与专论: 白质消融性白质脑病研究进展[J].生物化学与生物物理进展,2022,49(11):2099-2106

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  • 收稿日期:2022-07-31
  • 最后修改日期:2022-10-11
  • 接受日期:2022-08-31
  • 在线发布日期: 2022-11-22
  • 出版日期: 2022-11-20