Background

Alzheimer’s disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age.

Objectives

To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants.

Methods

Biomarkers of amyloid-β deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS).

Results

We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases.

Conclusions

This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results.

中文翻译：

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阿尔茨海默氏病的单例披露新的和旧的遗传“熟人”

背景

阿尔茨海默氏病（AD）是最常见的年龄相关性痴呆。除了典型的发作性记忆删除症状外，非典型性AD病例也越来越多地被识别，通常在老年期。

目标

为六名患有一个或多个奇异特征的AD患者提供广泛的临床和遗传学特征，包括发病年龄，非典型表型和疾病进展速度。通过审查相关文献并访问可公开获得的数据库，我们旨在评估已鉴定遗传变异的频率和重要性。

方法

除了神经和神经心理学评估，广泛的实验室分析和神经放射学数据外，还使用淀粉样β沉积和神经变性的生物标记物建立可能的AD的体内诊断。考虑到大多数病例的早发，我们假设遗传确定了AD，并通过Sanger测序和下一代测序（NGS）进行了广泛的遗传分析。

结果

我们公开的两个已知的错义变异体，一个在PSEN1和其他在PSEN2，和在一个新的无声变体PSEN2。最值得注意的是，我们通过NGS鉴定了其他痴呆相关基因中的其他几个变体。其中一些从未在任何对照或疾病数据库中报告过，它们代表了我们病例的独特变体。

结论

这项工作强调了在非典型痴呆病例中难以进行可靠的体内诊断的困难。此外，通过NGS方法进行的更广泛的遗传分析在特定情况下可能是有用的，特别是当对迄今已知的AD致病基因的研究产生阴性或矛盾的结果时。