中国早发性家族性阿尔茨海默病一家系淀粉样前体蛋白基因突变

Identification of a rare amyioid precursor protein gene mutation in a Chinese family with early-onset familial Alzheimer＇ s disease

目的研究1个中国早发性家族性阿尔茨海默病（EOFAD）家系的临床表型及存在的基因突变。方法收集1个EOFAD家系，分析2例患者的临床表现及辅助检查结果。采集2例患者及其他家庭成员的血样，提取基因组DNA，采用直接测序法进行淀粉样前体蛋白（APP）基因第16、17外显子、早老素1基因和早老素2基因检测。结果该家系中2例患者发病年龄较早，均缓慢起病，逐渐进展。首发症状为记忆力减退，Ⅱ3有发作性眨眼；Ⅱ5性格改变明显，病程中曾出现尿便障碍。2例患者的头部CT和MRI脑萎缩明显，以双侧颞叶为著。Ⅱ3的脑电图存在异常慢波。2例患者进行MMSE和蒙特利尔认知评估（MoCA）量表测试，提示为中重度智能减退。2例患者APP基因第17外显子中第2343位碱基发生突变（G—A），使编码APP的第715个密码子由GTG变为ATG，导致缬氨酸变为甲硫氨酸，发生V715M突变。Ⅱ1、Ⅱ3、Ⅱ5、Ⅲ1ApoE基因型为ε4／ε4，II9ApoE基因型为ε2／ε4。结论该家系APP基因发生V715M突变，证实在中国人群存在这一突变现象，并且导致发病，提示对可疑阿尔茨海默病患者或家系进行基因检测时不要遗漏该突变位点。

Objective To analyze the phenotype and genatics in a Chinese family with early-onset familial Alzheimer＇ s disease（EOFAD）. Methods Peripheral blood were collected in available members in the family and genomic DNA was extracted. PCR-sequeneing of exon 16 and exon 17 of the amyloid precursor protein（APP） gene, presenilin 1 （ PSEN1 ）, and presenilin 2 （ PSEN2 ） was performed. Results At age 40, two EOFAD patients （ siblings ） in the family developed an insidious onset of difficulties in memory. One （ Ⅱ 3 in the pedigree） showed blinking. The other （ Ⅱ5 ） showed irritability and bradykinesia. Progressive diffuse coritcal atrophy in bilateral temporal cortex was observed. Moderate diffuse cerebral dysfunction was observed in Ⅱ3 by the electroencephalogram study and neuropsychological assessments. Sequencing revealed that both patients were heterozygous for a mutation c. 2343 G 〉 A in exon 17 of APP, causing the amino acid substitution Val715Met. Four members （ Ⅱ1 , Ⅱ3, Ⅱ5 and Ⅲ1 ） were homozygous for ApoE ε4 allele. Ⅱ 9 was ε2/ε4. Conclusions This study identified a mutation, Val715Met in the APP gene in Chinese patients with EOFAD. We suggest screening for APP gene mutations in Chinese patients with EOFAD.