GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy
GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy
复制标题
DOI：
10.1212/01.wnl.0000223832.66286.e4
复制
发表时间：
2006-07-25
期刊：
影响因子：
9.9
通讯作者：
Zeviani, M.
中科院分区：
文献类型：
--
作者：
Bugiani, M.;Al Shahwan, S.;Zeviani, M.
背景：Pelizaeus-Merzbacher样病(PMLD)是一种遗传性低髓鞘细胞性白质脑病，起病于婴幼儿早期。与Pelizaeus-Merzbacher病(PMD)一样，PMLD的临床特征是眼球震颤、小脑性共济失调和痉挛，这是由于脑部永久性缺乏髓鞘沉积所致。编码连接蛋白47(Cx47)的GJA12基因突变最近在5例常染色体隐性遗传性PMLD儿童中被报道。目的：探讨GJA12基因突变对常染色体隐性遗传性多发性骨髓瘤(PMLD)的影响，明确其临床和神经影像特征。结果：作者对来自意大利、巴基斯坦和沙特阿拉伯的另外10个PMLD家系进行了GJA12突变筛查。在分布于10个家系中的3个家系的12个突变案例中发现了3个新的纯合子GJA12突变。这些突变根据常染色体隐性性状与疾病分离，包括一个错义(G236S)和两个无义(L281fs285X和P131fs144X)变化。结论：在非常大的家系中发现了预测异常和截短多肽合成的纯合子突变，以及它们与疾病的紧密分离，清楚地表明Cx47功能的丧失是疾病的原因。与GJA12相关的Pelizaeus-Merzbacher样病的表型与Pelizaeus Merzbacher病相似。然而，在MRI上，症状进展较慢、认知功能较好地保留以及皮质脊髓束部分髓鞘形成是明显的特征，这有助于鉴别诊断。
Background: Pelizaeus-Merzbacher-like disease (PMLD) is an inherited hypomyelinating leukoencephalopathy with onset in early infancy. Like Pelizaeus-Merzbacher disease (PMD), PMLD is characterized clinically by nystagmus, cerebellar ataxia, and spasticity, due to a permanent lack of myelin deposition in the brain. Mutations in the GJA12 gene, encoding connexin 47 (Cx47), were recently reported in five children with autosomal recessive PMLD. Objectives: To evaluate the impact of mutations in the GJA12 gene in, and define the clinical and neuroimaging features of, autosomal recessive PMLD. Results: The authors screened for GJA12 mutations in 10 additional PMLD families originating from Italy, Pakistan, and Saudi Arabia. Three novel homozygous GJA12 mutations were identified in 12 mutant cases distributed in 3 of 10 families. The mutations segregated with the disease according to an autosomal recessive trait and included one missense (G236S) and two nonsense (L281fs285X and P131fs144X) changes. Conclusions: The identification of homozygous mutations predicting the synthesis of aberrant and truncated polypeptides, and their tight segregation with the disease in very large families, clearly demonstrate that the loss of Cx47 function is the cause of the disease. The phenotype of GJA12-related Pelizaeus-Merzbacher-like disease is fairly homogeneous and similar to that of Pelizaeus Merzbacher disease. However, slower progression of symptoms, greater preservation of cognitive functions, and partial myelination of corticospinal tracts at MRI were distinctive features, which could help in the differential diagnosis.