Bird T D, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, Peskind E, Lampe T H, Nemens E, Boyer P J, Schellenberg G D
Department of Neurology, University of Washington, and Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, USA.
Brain. 1999 Apr;122 ( Pt 4):741-56. doi: 10.1093/brain/122.4.741.
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.
我们研究了三个患额颞叶痴呆的独立家族(分别命名为D、F和G家族),这些家族的tau基因第10外显子存在相同的分子突变(P301L)。这些家族具有许多共同的临床特征,包括行为异常、执行功能缺陷、语言障碍、相对保留的构建能力以及影像学研究显示的额颞叶萎缩。然而,D家族的平均发病年龄比F和G家族更早,疾病持续时间更短(分别为49.0岁和5.1年,而F和G家族为61 - 64岁和7.3 - 8.0年)。D家族和F家族的两名成员进行了神经病理学研究,结果显示脑叶萎缩,但D家族的大脑有明显且弥漫的圆形、神经元内神经原纤维缠结,而F家族未见此类情况。F家族的大脑有B型Pick病典型的气球样神经元,D家族未发现。D家族的第二次尸检显示脑干有神经原纤维缠结,其分布与进行性核上性麻痹相似。这三个家族表明,tau蛋白基因第10外显子微管结合结构域的错义突变可导致伴有额颞叶萎缩和微观tau病理学改变的严重行为异常。然而,这些家族的研究结果也强调,在相同突变背景下,其他未明确的环境和/或遗传因素必定会导致重要的表型变异。载脂蛋白E基因型似乎不是影响该疾病发病年龄的此类因素。