Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Dongcheng District, Beijing, 100730, People's Republic of China.
J Mol Neurosci. 2021 May;71(5):1015-1022. doi: 10.1007/s12031-020-01723-4. Epub 2020 Oct 1.
Frontotemporal dementia (FTD) is a heterogeneous disease both clinically and pathologically. Genetic mutation in microtubule-associated protein tau (MAPT) is the most common cause of FTD, and the phenotype is related to the mutation location. However, the phenotype and genotype correlation varies somewhat among different cohorts and ethnicities. Whole-genome next-generation sequencing (NGS) was carried out for 1351 patients with dementia at Peking Union Medical College Hospital. MAPT variations classified as pathogenic and of uncertain significance were identified. Demographic information, clinical presentations, and neuroimaging were collected, and the phenotype-genotype correlation was analyzed with a concurrent literature review. Twenty-four patients were enrolled; 8 patients carrying the D177V mutation are discussed separately. The average onset age was young, and most of them had a positive family history. Cognitive dysfunction, behavior, and personality changes as well as aphasia were the most common presentations. Most structural MRIs showed asymmetrical atrophy of the temporal lobe, with/without similar changes in the frontal lobe. L266V carriers presented with youngest onset typical behavior variant FTD or aphasia; P301L carriers presented with behavior variant FTD or aphasia. Functional MRI and molecular imaging also showed that the involved areas were similar to those with structural atrophy. D296N carriers presented atypical parkinsonism and cognitive dysfunction at older ages. Eight D177V carriers had extraordinarily different manifestations. The clinical phenotype of most of them was not FTD, though cerebral vascular lesions were obvious in some of them. MAPT mutation is rare in Chinese dementia patients. The phenotype and genotype correlation is specific and overlaps. The D177V mutation is possibly not directly pathogenic in our cohort. Some of the variants might increase the genetic risk of neurodegenerative diseases.
额颞叶痴呆（FTD）在临床和病理上均具有异质性。微管相关蛋白 tau（MAPT）中的基因突变是 FTD 的最常见原因，表型与突变位置相关。然而，表型与基因型的相关性在不同的队列和种族中存在一定差异。对北京协和医院的 1351 例痴呆患者进行了全基因组下一代测序（NGS）。鉴定了归类为致病性和意义未明的 MAPT 变异。收集了人口统计学信息、临床表现和神经影像学资料，并进行了表型-基因型相关性分析，并同时进行了文献复习。共纳入 24 例患者，其中 8 例携带 D177V 突变，将单独讨论。平均发病年龄较早，大多数患者有阳性家族史。认知功能障碍、行为和人格改变以及失语症是最常见的表现。大多数结构 MRI 显示颞叶不对称性萎缩，伴/不伴额叶类似改变。L266V 携带者表现为发病年龄最小的典型行为变异型 FTD 或失语症；P301L 携带者表现为行为变异型 FTD 或失语症。功能 MRI 和分子影像学也显示受累区域与结构萎缩相似。D296N 携带者在较晚年龄出现非典型帕金森病和认知功能障碍。8 例 D177V 携带者表现出非常不同的表现。他们中的大多数人的临床表型不是 FTD，尽管其中一些人的脑血管病变明显。MAPT 突变在中国痴呆患者中较为罕见。表型与基因型的相关性是特定的，存在重叠。在我们的队列中，D177V 突变可能不是直接致病的。一些变体可能会增加神经退行性疾病的遗传风险。
