van der Knaap Marjo S, van Berkel Carola G M, Herms Jochen, van Coster Rudy, Baethmann Martina, Naidu Sakkubai, Boltshauser Eugen, Willemsen Michèl A A P, Plecko Barbara, Hoffmann Georg F, Proud Christopher G, Scheper Gert C, Pronk Jan C
Department of Child Neurology, Free University Medical Center, Amsterdam, The Netherlands.
Am J Hum Genet. 2003 Nov;73(5):1199-207. doi: 10.1086/379524. Epub 2003 Oct 17.
Leukoencephalopathy with vanishing white matter, also called "childhood ataxia with central nervous system hypomyelination," is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile-onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.
伴脑白质消失的白质脑病，也称为“伴中枢神经系统髓鞘形成低下的儿童共济失调”，是首例与编码真核起始因子eIF2B亚基的五个基因中任何一个或任何翻译因子发生突变相关的人类疾病。eIF2B在身体所有细胞中对于蛋白质合成以及在不同应激条件下对这种蛋白质合成的调节至关重要。令人惊讶的是，尽管最近已表明卵巢功能衰竭可能伴随白质脑病，但据报道eIF2B基因突变仅导致脑白质异常。另一个令人惊讶的观察结果是，除了克里白质脑病（一种与eIF2B基因之一的特定突变相关的疾病，其发病总是在生命的第一年内）外，该疾病的发病从幼儿期到成年期各不相同。我们分析了9例产前或婴儿早期发病的脑病且早亡患者的eIF2B基因，发现其中8例患者存在突变。除了严重脑病的体征外，我们还发现羊水过少、宫内生长迟缓、白内障、胰腺炎、肝脾肿大、肾发育不全和卵巢发育不全。到目前为止，尚未发现基因型与表型之间存在相关性的证据，但在我们的患者以及克里脑病患者中，受影响的兄弟姐妹中始终存在严重的表型，这表明基因型对表型有影响。
