PSEN1 G417S mutation in a Chinese pedigree causing early-onset parkinsonism with cognitive impairment

• Published in: Neurobiology of aging Vol. 115; pp. 70 - 76
• Main Authors: Jiang, Li, Qin, Yan, Zhao, Yu-Wen, Zeng, Qian, Pan, Hong-Xu, Liu, Zhen-Hua, Sun, Qi-Ying, Xu, Qian, Tan, Jie-Qiong, Yan, Xin-Xiang, Li, Jin-Chen, Tang, Bei-Sha, Guo, Ji-Feng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2022
• Subjects: Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; China; Cognitive Dysfunction - genetics; Cognitive impairment; Humans; Mutation - genetics; Parkinsonian Disorders - complications; Parkinsonian Disorders - diagnostic imaging; Parkinsonian Disorders - genetics; Parkinsonism; Pedigree; Presenilin-1 - genetics; PSEN1; Whole exome sequencing; China; Parkinsonism; PSEN1; Whole exome sequencing; Alzheimer's disease; Cognitive impairment
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2022.03.016

•PSEN1 G417S mutation was firstly identified in a Chinese pedigree and classified as pathogenic.•Early-onset parkinsonism is relatively rare in Alzheimer's disease.•Our findings provided the clinical evidence of cerebrovascular factors in the pathogenesis of AD. Presenilin 1 (PSEN1) mutations are a major cause of familial Alzheimer's disease. The pathogenic variant, PSEN1 p.G417S, has been reported to be associated with spastic paraparesis and cotton wool plaques in Japan. Here, we report a 3 generation Chinese pedigree that included 10 patients presenting with early-onset and rapid progression of parkinsonism with cognitive impairment in their third or fourth decade of life. Three additional living patients developed different degrees of cognitive impairment, without movement disorders. Magnetic resonance imaging of the brain showed white matter hyperintensities, multiple microbleeds, and enlarged perivascular spaces. Whole exome sequencing analysis of the proband detected the mutation, p.G417S, in PSEN1, which was completely co-segregated with the disease phenotype within the family by Sanger sequencing. 3D protein structures predicted that the mutation might influence contact with the lipid membrane and the interaction with beta-catenin. Our study provides insights into the heterogeneity in clinical presentation and imaging associated with mutations in PSEN1.