Moreno Fermin, Indakoetxea Begoña, Barandiaran Myriam, Caballero María Cristina, Gorostidi Ana, Calafell Francesc, Gabilondo Alazne, Tainta Mikel, Zulaica Miren, Martí Massó José F, López de Munain Adolfo, Sánchez-Juan Pascual, Lee Suzee E
Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute Carlos III, Madrid, Spain.
PLoS One. 2017 Jun 8;12(6):e0178093. doi: 10.1371/journal.pone.0178093. eCollection 2017.
The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families.
We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked β-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability).
In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.
在18个受额颞叶痴呆（FTD）影响的巴斯克家族中，已鉴定出c.709-1G>A GRN突变和p.A152T MAPT变体的共现情况。我们旨在研究p.A152T MAPT变体对这些巴斯克GRN家族临床和神经病理学特征的影响。
我们比较了14名携带c.709-1G>A GRN突变（GRN+/A152T-）的患者与21名同时携带c.709-1G>A GRN突变和p.A152T MAPT变体（GRN+/A152T+）的患者的临床特征。比较了两组之间的神经心理学数据（n = 17）和血浆前颗粒蛋白水平（n = 23），并对7名受试者进行了神经病理学研究。我们对两个最大家族中的六个短串联重复标记进行了基因分型。通过分析单倍型块中的连锁不平衡衰减，我们估计了同时携带这两种遗传变异的第一个祖先出现的时间。GRN+/A152T+和GRN+/A152T-患者具有相似的临床和神经心理学特征以及血浆前颗粒蛋白水平。所有患者均被诊断为FTD疾病，包括行为变异型FTD或非流利/语法缺失型原发性进行性失语，并且具有相似的神经心理学缺陷模式，主要表现为执行功能、记忆和语言方面的缺陷。所有7名有脑尸检结果的参与者（6名GRN+/A152T+，1名GRN+/A152T-）均表现为伴有TDP-43包涵体的额颞叶变性（A型分类），这是GRN携带者的特征。此外，所有7名参与者均表现出轻度至中度的tau包涵体负担：5例缺乏β-淀粉样蛋白病理，2例有阿尔茨海默病病理。一个个体中这两个基因的共现是近期发生的，估计第一个GRN+/A152T+个体的出生时间在过去50代以内（95%概率）。
在我们的样本中，p.A152T MAPT变体似乎对GRN携带者的临床表型没有明显影响。在这些GRN携带者中，p.A152T是否赋予tau病理超出预期的倾向仍是一个悬而未决的问题。
