Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Getingevägen 4, 221 85, Lund, Sweden.
Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Diagnostic Radiology, Getingevägen 4, 221 85, Lund, Sweden.
Alzheimers Res Ther. 2018 Jan 9;10(1):2. doi: 10.1186/s13195-017-0330-2.
The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer's disease-like clinical features.
We compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes.
For all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer's disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-β pathology was absent.
Dominance of 4R over three-repeat (exon 10-) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.
MAPT c.1216C > T（p.Arg406Trp；R406W）突变是已知的导致与染色体 17 上的 tau 相关的额颞叶痴呆伴帕金森病，具有阿尔茨海默病样临床特征的原因。
我们编译了一个新的瑞典家族中具有 R406W 突变的临床数据。对 7 名家族成员进行了长达 22 年的纵向随访。对 6 名家族成员进行了影像学检查，对 3 名家族成员进行了神经病理学检查。我们系统地回顾了文献，并编译了 63 名先前描述的 R406W 杂合子和 3 名纯合子的临床、影像学和神经病理学数据。
所有病例的中位发病年龄为 56 岁，中位病程为 13 年。记忆障碍是最常见的症状，行为障碍和语言障碍较少见，帕金森病罕见。疾病进展通常较为缓慢。最常见的临床诊断为阿尔茨海默病。R406W 纯合子的发病年龄更早，行为症状和帕金森病的频率更高。在新的瑞典家族中，一致的影像学发现是腹内侧颞叶萎缩，这在疾病早期阶段也很明显，表现为侧副沟变宽，随之而来的是海马旁回萎缩。与先前发表的 R406W 携带者不同，来自新家族的所有 3 名尸检患者都表现出与进行性核上性麻痹相似的神经病理学特征，以四重复（外显子 10+）tau 异构体（4R）tau 病为主，基底-内侧颞叶神经原纤维缠结加重。淀粉样β病理学不存在。
4R 对三重复（外显子 10-）tau 异构体的优势与先前报道的 R406W 患者的情况相反，并且不能用两个尸检患者中存在 H1/H2 单倍型充分解释。R406W 患者通常表现出疾病的长病程，伴有明显的记忆缺陷。我们的神经病理学结果和影像学发现都显示，在这种疾病中，腹内侧颞叶广泛受累。我们建议，该区域可能是该疾病中 tau 沉积的起源点，具有相对孤立的 tau 病。
