A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L)
A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L)
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DOI：
10.1093/brain/122.4.741
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发表时间：
1999-04-01
期刊：
影响因子：
14.5
通讯作者：
Schellenberg, GD
中科院分区：
文献类型：
--
作者：
Bird, TD;Nochlin, D;Schellenberg, GD
我们调查了三个不同的额颞叶痴呆家族（指定为 D、F 和 G），它们的 tau 基因外显子 10（P301L）具有相同的分子突变。这些家族有许多共同的临床特征，包括行为异常、执行功能缺陷、语言缺陷、相对保留的构建能力和影像学研究中的额颞叶萎缩。然而，D 家族的平均发病年龄较早，持续时间较短。 比家庭 F 和 G 的疾病患病率更高（分别为 49.0 和 5.1 岁，分别为 61-64 和 7.3-8.0 岁），家庭 D 和 F 的两名成员进行了神经病理学研究，表明脑叶萎缩，但家庭 D 的大脑具有家庭 F 中未见的突出且弥漫的圆形、神经元内、神经原纤维缠结。家庭 F 的大脑具有典型的皮克病 B 型气球状神经元，家庭中未发现这种神经元 D，D 家族的第二次尸检显示，脑干中存在神经原纤维缠结，其分布与进行性核上性麻痹中发现的分布相似。这三个家族证明，tau 蛋白基因的外显子 10 微管结合域的错义突变可产生严重的行为异常，伴有额颞叶萎缩和微观 tau 病理学。然而，这些家族的研究结果还强调，在相同突变（载脂蛋白 E）的背景下，其他未识别的环境和/或遗传因素必定会产生重要的表型变异。 基因型似乎不是影响这种疾病发病年龄的因素。
We investigated three separate families (designated D, F and G) with frontotemporal dementia that have the same molecular mutation in exon 10 of the tau gene (P301L), The families share many clinical characteristics, including behavioural aberrations, defective executive functions, language deficits, relatively preserved constructional abilities and frontotemporal atrophy on imaging studies, However, Family D has an earlier mean age of onset and shorter duration of disease than Families F and G (49.0 and 5.1 years versus 61-64 and 7.3-8.0 years, respectively), Two members of Families D and F had neuropathological studies demonstrating lobar atrophy, but the brain from Family D had prominent and diffuse circular, intraneuronal, neurofibrillary tangles not seen in Family F. The brain from Family F had ballooned neurons typical of Pick's disease type B not found in Family D, A second autopsy from Family D showed neurofibrillary tangles in the brainstem with a distribution similar to that found in progressive supranuclear palsy. These three families demonstrate that a missense mutation in the exon 10 microtubule-binding domain of the tau protein gene can produce severe behavioural abnormalities with frontotemporal lobar atrophy and microscopic tau pathology, However, the findings in these families also emphasize that additional unidentified environmental and/or genetic factors must be producing important phenotypic variability on the background of an identical mutation, Apolipoprotein E genotype does not appear to be such a factor influencing age of onset in this disease.