Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.

在患有进行性疾病的患者中发现了包含MAPT基因的 17q21.31 染色体区域的微复制，该基因编码 Tau 蛋白，最初的特征是严重的记忆障碍，伴有或不伴有临床上模仿阿尔茨海默病的行为变化。独特的神经病理学报告显示原发性 tau 病变，无法一致归类为给定的已知亚型，显示 4R 和 3R tau 包涵体，主要位于颞叶皮质亚区和基底神经节内，没有淀粉样蛋白沉积。最近，两名具有相同重复的受试者被报告患有非典型锥体外系综合征和步态障碍。破译与MAPT相关的表型谱重复，我们研究了来自九个家庭的十个携带者，包括两个新的无关先证者，收集临床（n  = 10），脑脊液（n  = 6），MRI（n  = 8），多巴胺转运蛋白扫描（n  = 4），功能（n  = 5)、淀粉样蛋白 ( n  = 3) 和 Tau-tracer ( n  = 2) PET 成像数据以及神经病理学检查 ( n = 4)。发病年龄从 37 岁到 57 岁不等，8/10 患者有显着的情景记忆障碍，其中 4 人伴有行为改变，而 2 例患者出现非典型锥体外系综合征伴步态障碍，其中 1 例伴有认知缺陷。淀粉样蛋白成像呈阴性，但 Tau 成像显示主要在颞中皮质有明显的沉积物。4/4 患者发现多巴胺能去神经支配，其中 3 名没有锥体外系症状。神经病理学检查仅显示 Tau 免疫反应性病变。分布、方面和 4R/3R tau 聚集体组成表明从主要是 3R（主要是与认知和行为变化密切相关的皮质沉积物）到主要是在基底神经节和中脑中的主要是 4R 沉积物的光谱，在有突出的锥体外系综合征的患者中。最后，我们在 HEK 生物传感器细胞中进行了体外接种实验。三种匀浆诱导聚集体的形态特征MAPT重复携带者显示出由 Pick 病匀浆和进行性核上性麻痹病例诱导的致密/颗粒比率。这些结果表明，MAPT重复导致与多种临床和神经病理学特征相关的原发性 tauopathy。