摘要分析早发型家族性阿尔茨海默病一家系的临床资料,并对该家系进行致病基因突变分析.方法 收集2018年10月就诊于河南省人民医院神经内科、临床诊断为早发型阿尔茨海默病的先证者及其家系成员临床资料.对先证者血样进行人类全外显子测序,遗传变异的致病性评估依据美国医学遗传学与基因组学学会于2015年发布的《序列变异解读标准和指南》,并对家系中部分成员及50例散发性阿尔茨海默病和50名家系正常个体进行一代验证,对包括先证者在内的10名家系成员进行载脂蛋白E(APOE)分型检测.结果 家系先证者表现为记忆力下降、视空间障碍、言语重复、人格改变、精神行为异常.基因检测发现先证者淀粉样前体蛋白基因17号外显子第717位点密码子发生p.V717I突变,家系中另5位成员亦存在该位点突变.10名家系成员APOE分型检测均为ε3/ε3型.未在50例散发性阿尔茨海默病患者和50名家系外正常个体发现该突变.先证者头颅磁共振成像(MRI)平扫示双侧海马萎缩,左侧为著,头颅磁共振血管造影未发现明显异常.先证者妹妹头颅MRI示全脑萎缩,双侧海马萎缩.结论 在早发型家族性阿尔茨海默病一家系6例患者中鉴定出β淀粉样前体蛋白基因p.V717I致病性突变,且该突变存在家系共分离现象,这种发现对中国人群早发型阿尔茨海默病研究具有重要意义.

abstractsObjective To analyze the clinical data of a family with early?onset familial Alzheimer′s disease and to analyze the mutation of the pathogenic gene in the family. Methods The clinical data of a proband who was clinically diagnosed as early?onset Alzheimer′s disease in the Department of Neurology, People′s Hospital of Zhengzhou University in October 2018 and her family members were collected. Moreover, whole exome sequencing was performed on blood sample from the proband, then its deleterious effects were assessed according to the Standards and guidelines for the interpretation of sequence variants, a joint consensus recommendation of the American College of Medical Genomics. Subsequently, the strong pathogenic mutation was validated by Sanger sequencing in the some members of the family and 50 sporadic Alzheimer′s disease and 50 normal individuals of the family. Apolipoprotein E (APOE) typing of 10 family members was all epsilon 3/epsilon 3. Results The proband in this family showed decreased memory, visual space disorder, verbal repetition, personality change and abnormal mental behavior. The mutation at codon 717 of exon 17 of the proband amyloid precursor protein gene was detected by gene detection. The mutation at codon 717 of exon 17 of the proband beta?amyloid precursor protein gene was also found in the other five members of the family. The mutation was not found in 50 sporadic Alzheimer′s disease patients and 50 normal individuals outside the family. The proband′s head magnetic resonance imaging (MRI) showed bilateral hippocampal atrophy on plain scan, especially on the left side. No obvious abnormality was found in the head magnetic resonance angiography. The head MRI of the proband′s sister showed brain atrophy and bilateral hippocampal atrophy. Conclusions The study identified the pathogenic mutation of the beta?amyloid precursor protein gene p. V717I in six patients of a family with early?onset familial Alzheimer′s disease, and the mutation showed a phenomenon of family segregation. This finding is of great significance to the study of early?onset Alzheimer′s disease in Chinese population.