Abstract：
Familial Alzheimer\'s disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aβ protein deposition. The cerebrospinal fluid amyloid protein test showed Aβ42/Aβ40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.
摘要：
家族性阿尔茨海默病(AD)是一种由常染色体显性突变引起的罕见疾病。APP（编码淀粉样前体蛋白），PSEN1（编码早熟蛋白1），PSEN2(编码早老素2)是引起显性遗传性AD的最常见基因。这项研究旨在证明中国早发AD谱系表现为进行性记忆障碍，失用症,视觉空间障碍，精神行为障碍,新的APP基因突变和人格改变。这个家庭有四个病人，三个携带和三个正常的家庭成员。先证者接受了脑部磁共振成像（MRI），18F-氟脱氧葡萄糖正电子发射断层扫描（18F-FDG-PET），脑脊液淀粉样蛋白检测，18F-florbetapir（AV-45）正电子发射计算机断层扫描（PET）成像，全外显子组测序和Sanger测序。脑部MRI图像显示脑萎缩，尤其是在内嗅皮层，颞叶海马,侧脑室扩张.FDG-PET显示额颞叶低代谢,顶叶,和海马区。18F-florbetapir(AV-45)PET显像显示大脑皮质Aβ蛋白沉积。脑脊液淀粉样蛋白检测显示Aβ42/Aβ40比值降低,病理性磷tau水平增加。全外显子组测序检测到一个新的错义突变的密码子671（M671L），这是淀粉样前体蛋白外显子16的位置2011（c.2011A>T）的杂合A到T点突变，导致蛋氨酸被亮氨酸取代。在该家族中验证了共分离分析。在3名患者中发现了突变，3个临床正常家庭成员，但不是在其他三个未受影响的家庭成员中，100名无关的正常人,或100名散发性AD患者。该突变可能在中国汉族早发性AD家族中具有致病性和新颖性。
