摘要：

目的 报道2例PSEN1基因变异致早发性家族性阿尔茨海默病患者家系，结合文献总结我国早发性家族性阿尔茨海默病PSEN1基因变异位点及临床和遗传学特征。方法与结果 收集2例就诊于首都医科大学附属北京天坛医院的早发性家族性阿尔茨海默病患者家系的临床资料，对先证者行外周血DNA遗传学检测，并检索已报道的中国PSEN1基因变异致早发性家族性阿尔茨海默病病例。例1先证者，45岁发病，首发表现为记忆力减退；头部MRI显示全脑皮质及双侧海马轻度萎缩；基因检测显示PSEN1基因外显子6 c.488A>G（p.His163Arg）致病性突变；家系中共3人有类似表现，该家系明确为早发性家族性阿尔茨海默病家系。例2先证者，42岁发病，首发表现为记忆力和工作能力下降；头部MRI显示全脑皮质萎缩，双侧海马萎缩，以左侧显著；基因检测显示PSEN1基因外显子5 c.344A>G（p.Tyr115Cys）致病性突变；家系中共6人有类似症状，该家系明确为早发性家族性阿尔茨海默病家系。目前报道的中国PSEN1基因变异致早发性家族性阿尔茨海默病共40家系（包括本研究两家系），致病突变位点38个，发病年龄21~62岁，病程4~10年，约87.50%（35/40）患者以进行性记忆力减退发病，可迅速累及多个认知域，部分患者可伴有锥体外系症状、癫癎发作、耳部症状，进展迅速。结论 PSEN1基因c.488A>G和c.344A>G位点突变可导致早发性家族性阿尔茨海默病，其中c.344A>G突变位点为国内首次报道。早发性家族性阿尔茨海默病患者发病早，进展迅速，首发症状可不典型，基因检测在疾病诊断中具有重要作用。

关键词: 阿尔茨海默病, 早老素1, 基因, 突变, 系谱

Abstract:

Objective To report 2 pedigrees of early -onset familial Alzheimer's disease (EOFAD) caused by PSEN1 gene mutation, review previous studies and summarize the PSEN1 gene mutation sites, clinical presentation and genotype characteristics of EOFAD in China. Methods and Results The clinical data of 2 pedigrees with EOFAD from Beijing Tiantan Hospital, Capital Medical University were collected. Genomic DNA from peripheral venous blood of the proband was screened. Search the reported Chinese cases of EOFAD caused by PSEN1 gene mutation. In the Case 1 family, there were 3 members with memory loss, including the proband, onset at the age of 45. His head MRI showed mild atrophy of the cerebral cortex and bilateral hippocampus. A c.488A > G (p.His163Arg) pathogenic mutation in the exon 6 of PSEN1 gene was found, proving the diagnosis. In the Case 2 family, there were 6 members with memory and working competence loss, including the proband, onset at the age of 42. Head MRI showed whole cerebral cortical atrophy and bilateral hippocampal atrophy, obviously on the left side. A c. 344A > G (p. Tyr115Cys) pathogenic mutation in the exon 5 of PSEN1 gene was found, proving the diagnosis. A total of 40 cases (including this 2 cases) of EOFAD patients caused by PSEN1 gene mutation in China were enrolled. Thirty-eight pathogenic mutation sites were reported. The age of onset ranged from 21 to 62 years old, and the course of disease ranged from 4 to 10 years. About 87.50% (35/40) of the patients' onset manifestation was progressive memory loss and then rapidly with multiple cognitive domains involved. Some patients manifested with extrapyramidal symptoms, epilepsy or ear symptoms. Conclusions c.488A > G and c.344A > G mutations in the PSEN1 gene were identified to cause EOFAD, and c.344A > G mutation is the first report in China. EOFAD occurs early and progresses rapidly, and sometimes the initial symptoms may be atypical. Therefore, gene detection plays an important role in the diagnosis of the disease.

Key words: Alzheimer disease, Presenilin-1, Genes, Mutation, Pedigree