Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
Alzheimer Dis Assoc Disord. 2021;35(3):208-213. doi: 10.1097/WAD.0000000000000438.
BACKGROUND/PURPOSE: Sporadic early-onset Alzheimer disease (sEOAD) and its visual variant, posterior cortical atrophy (PCA), have a disease onset at less than 65 years of age with no familial aggregation. The etiology and genetic basis of these diseases remain poorly understood. Our study aimed to identify additional mutations or variants associated with sEOAD and PCA and to further examine their genetic and phenotypic spectrums.
We performed whole-exome sequencing and analyzed the clinical and neuroimaging features of mutation carriers with 29 patients having sEOAD and 25 having PCA.
Nine rare damaging variants were identified in 4 patients with sEOAD and 3 with PCA. A novel mutation (p.A136V) in PSEN1 was identified in a patient with sEOAD and a likely pathogenic variant (p.M239T) was identified for PSEN2 in a patient with PCA. In addition, 7 rare damaging variants were detected in other genes related to neurodegenerative diseases. The patient carrying the PSEN1 p.A136V mutation presented with typical clinical and imaging features of sEOAD, and the PCA patient with the PSEN2 p.M239T mutation presented with visuospatial impairment as the initial symptom.
Our study expands the PSEN1 mutation spectrum of sEOAD and highlights the importance of screening PSEN1 and/or PSEN2 mutations in PCA patients.
背景/目的：散发性早发性阿尔茨海默病（sEOAD）及其视觉变异型后部皮质萎缩（PCA）的发病年龄小于 65 岁，且无家族聚集性。这些疾病的病因和遗传基础仍知之甚少。我们的研究旨在鉴定与 sEOAD 和 PCA 相关的其他突变或变体，并进一步研究它们的遗传和表型谱。
我们进行了全外显子组测序，并分析了 29 名 sEOAD 患者和 25 名 PCA 患者突变携带者的临床和神经影像学特征。
在 4 名 sEOAD 患者和 3 名 PCA 患者中发现了 9 种罕见的致病性变异。在一名 sEOAD 患者中发现了 PSEN1 中的新突变（p.A136V），在一名 PCA 患者中发现了 PSEN2 的可能致病变体（p.M239T）。此外，在其他与神经退行性疾病相关的基因中还检测到 7 种罕见的致病性变异。携带 PSEN1 p.A136V 突变的患者表现出典型的 sEOAD 临床和影像学特征，而携带 PSEN2 p.M239T 突变的 PCA 患者则以视觉空间障碍为首发症状。
我们的研究扩展了 sEOAD 的 PSEN1 突变谱，并强调了在 PCA 患者中筛查 PSEN1 和/或 PSEN2 突变的重要性。
