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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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A case report of a family with early-onset Alzheimer's disease

  • LI Chenping 1 ,
  • ZHANG Weiwei 1 ,
  • GUO Lina 1 ,
  • TANG Beisha 1, 2, 3 ,
  • JIAO Bin 1, 2, 3
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  • 1 Department of Neurology, Xiangya Hospital, Central South University
  • 2 Key Laboratory of Hunan Province inNeurodegenerative Disorders
  • 3 National Center Research Center of Geriatric Diseases of China

Received date: 2019-03-21

  Revised date: 2019-04-08

  Online published: 2019-09-25

Abstract

Objective: To determine the genetic diagnosis of a family with early-onset familial Alzheimer's disease(EOFAD) and analyze its clinical phenotypic characteristics. Methods: A family were clinically evaluated at department of neurology, Xiangya hospital, Central South University. Definite EOFAD diagnosis were established by combining history, clinical manifestation, physical examination, laboratory tests, neuropsychological assessments, imaging. Meantime, we screened causative genes (PSEN1, PSEN2, APP) of Alzheimer's disease (AD) in this family with EOFAD. Results: In this family, there were 3 patients in total, 1 carrier. The proband displayed slow reaction initially, memory decline, and subsequently presented language expression disorder and personality change. Sanger sequencing showed that the proband carried missense mutation of PSEN1 gene (c. 604A> T, p. I202F). The mutation was isolated in the family and was not detected in 400 age, geographical ancestry matched normal controls and various databases. SIFT, Polyphen2, Mutation Taster and FATHMM predicted the pathogenicity of the mutation. Conclusion: We firstly reported the mutation of this locus in Han population. Our study expand the PSEN1 mutation spectrum and help to enrich the characterization of clinical phenotype in EOFAD associated to PSEN1 mutations. This case reminds us that the early onset AD patients with atypical clinical manifestation should be cautious in diagnosis to avoid misdiagnosis.

Cite this article

LI Chenping , ZHANG Weiwei , GUO Lina , TANG Beisha , JIAO Bin . A case report of a family with early-onset Alzheimer's disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2019 , 2(3) : 420 -425 . DOI: 10.3969/j.issn.2096-5516.2019.03.006

阿尔茨海默病(Alzheimer's disease, AD)是老年痴呆中最主要的痴呆类型,其病理学特征是β淀粉样蛋白 (Aβ)沉积形成的细胞外老年斑(senile plaques)、 tau蛋白过度磷酸化形成的神经原纤维缠结(neurofibrillary tangles, NFTs)、神经元丢失伴胶质细胞增生、淀粉样蛋白血管病及海马神经元颗粒空泡变性等[1]。家族性早发阿尔茨海默病(Early-onset Alzheimer's disease EOAD)发病年龄小于65岁[2],约占AD的5%。目前发现3个家族性EOAD的致病基因[3]:淀粉样前体蛋白基因(the amyloid precursor protein gene, APP)、早老 素1基因(presenilin 1, PSEN1)和早老素2基因 (presenilin 2, PSEN2)。PSEN1基因突变致病占EOFAD病例的50%左右,是最常见的致病基[4]。到目前为止,已经发现226种PSEN1基因的不同突变[5-6]。AD最常见的临床表现为记忆呈进行性下降,行为异常,最终发展为多认知域受累。然而,有些携带PSEN1基因的AD患者症状不典型,可表现为精神症状,痉挛性截瘫,共济失调,肌阵挛,癫痫等症状。本研究报道了一个汉族EOFAD家系携带PSEN1 基因(c. 604A> T, p. I202F )突变。

1 资料

1.1 病史情况

患者,郑某,女性,38岁,小学老师,大专文化。因“反应迟钝,记忆力下降2年”为主诉入院。患者两年前开始无明显诱因地出现反应迟钝、记忆力下降,主要为近记忆力下降:不记得刚刚讲过的话,不记得刚刚吃过的饭,远期记忆力相对保留。近一年来患者不喜交流,语言减少,表达能力下降,找词困难,能听懂别人说的话,但是不能完整表达自己的意思。近半年来患者动作迟缓,平时感兴趣的活动不再喜欢,易发脾气,在当地医院诊断为“抑郁症”,予“艾司西猷普兰10 mg/日”治疗2个月后未见明显好转患者自行停药。为明确诊断,家属遂将患者送入我院记忆障碍门诊。自发病以来,饮食睡眠较好,偶有嗜睡。二便正常。既往有慢性胃炎病史。个人史无特殊。婚育史:患者25岁结婚,育有1子,家庭和睦,丈夫与儿子身体健康。家族史:患者母亲(1:2)、三哥(11:3)、二姐(11:5)有痴呆相关病史。详见图1。具体表现为:患者母亲有记忆力下降病史,病程约10年,后期生活不能自理,因长期卧床肺部感染去世。患者三哥目前年龄54岁,48岁时渐起记忆力下降,伴精神异常,表现为被害妄想,怀疑周围的人在自己饭菜下毒,当地医院诊断为“精神分裂症”,予“利培酮”治疗(剂量和治疗时间不详),症状改善不明显。患者二姐目前年龄为50岁,45岁时起初症状表现为无故发脾气,摔坏衣物等行为异常,48岁时出现记忆力下降,未予重视,因此未就医诊治。
图1 郑某家系图。方框代表男性,圆圈代表女性,斜线代表已去世,黑色实心方框或 黑色实心圆圈代表患者,黑色箭头指向先证者。

1.2 体格检查

意识清楚,言语表达困难,注意力差,远记忆力尚保留,近记忆力差,计算力较差:连续计算100-7计算题中有3次错误,理解力尚保留,时间和空间定向力完整。患者行动迟缓。颅脑神经检查无阳性体征。四肢运动、感觉、反射正常。共济运动不配合。

1.3 辅助检查

1.3.1 实验室检查

血常规,尿常规,大便常规,肝肾功能,血脂,血糖,电解质,糖化血红蛋白,贫血四项,甲状腺功能,梅毒抗体、HIV抗体均无显著异常。

1.3.2 神经心理检查

对家系中3例患者和4例未发病者进行认知评估,评估内容主要包括:1)总体认知评估:简明精神状态量表(MMSE)、阿尔茨海默病认知为量表 (ADAS-cog )和临床痴呆评定量表(CDR); 2)精神行为评估:神经精神量表(NPI); 3)日常生活能力:日常生活能力量表(ADL); 4)语言评估:语音流畅性,语义流畅性,波士顿命名。详见表1
表1 家系中部分患者和正常人的神经心理学评估得分
项目 11:1 11:3 11:4 11:5 11:6 11:7 11:8
性别
年龄 59 54 51 50 43 41 38
是否患病
发病年龄 —— 48 45 36
MMSE 26 NA 25 13 28 28 9
ADAS-cog 6 NA 7 18 5 6 37
NPI 0 12 0 8 0 0 6
语音流畅性 9 NA 9 6 9 9 3
语义流畅性 7 NA 8 8 9 7 1
波士顿命名 20 3 20 9 22 19 5
ADL 20 30 20 28 20 20 36
CDR 0 2 0 1 0 0 2

注:简明精神状态量表(MMSE),阿尔茨海默病认知行为量表(ADAS-cog),神经精神量表(NPI),日常生活能力量表(ADL),临床痴呆评定量表(CDR),NA(无法完成)。

1.3.3 影像学检查

对家系中的两例患者11:8、11:5和正常对照11:6 进行头部MRI平扫,与正常对照相比,两例患者均有不同程度的脑萎缩,其中11:8患者有海马轻度萎缩。详见图2
图2 (A1-A3)11:8患者弥漫性脑皮质萎缩,额叶及海马萎缩明显,海马体积缩小,脑沟增宽,脑池增大,侧脑室周围脑白质变性。(B1-B3)11:5患者轻度脑萎缩,腔隙性脑梗死。(C1-C3 )正常对照11:6头部MRI平扫未见明显异常。

1.3.4 基因诊断

患者有痴呆家族史,利用Sanger Sequencing分析PSEN1, PSEN2和APP基因的所有外显子后,检测到家系中的3个患者均携带c. 604A> T, p. I202F突变,家系中的先证者儿子(111:13)为突变携带者,由于年龄较小,需继续追踪其认知变化。其他未发病者均未携带该突变。共收集到家系中未发病者4人(11:1、11:4、11:6、11:7)均未携带该突变。在400人及各大数据库[National Heart Blood and Lung Institute Exome Sequencing Project (ESP6500), 1000 Genomes Project (result in different dataset: Asian, 2012 Apr); CHB (Northern Chinese); JPT (Japanese); CHS (Southern Han Chinese)或 the Single Nucleotide Polymorphism Database (dbSNP137)][7]均未发现该突变,各个软件预测结果均为致病性,根据ACMG分级,判读为可能致病,详见图3
图3 分子诊断测序图:患者和携带者均携带PSEN1 c. 604A> T, p. I202F突变,正常对照不携带。

注:该碱基突变位点位于保守序列。在400例正常对照中未发现 该突变。SIFT功能预测该突变位点具有致病性。

1.4 治疗过程

3例患者中只有先证者具有服药依从性。因此,对患者认知功能进行了6个月和12个月的追踪。患者主要服用美金刚联合多奈哌齐治疗。第1周:5 mg 美金刚/日+5 mg多奈哌齐/ H ;第2周:5 mg美金刚/ 每日两次+5 mg多奈哌齐/日;第3周:10 mg美金冈/ 晨+5 mg美金刚/晚+5 mg多奈哌齐/日;第4周至今:10 mg美金刚/每日两次+5 mg多奈哌齐/日。患者目前已服用14个月,复查血常规,肝肾功能,心肌酶等指标,均无明显的副作用。经过追踪期的神经心理学 评估,治疗6个月和12个月后,患者的认知评估未显著改善。详见图4
图4 先证者(II:8)分别在治疗基线,6个月,12个月时的总体认知评估和日常生活能力评估。

2 讨论

目前已明确的阿尔茨海默病致病基因为PSEN1, PSEN2和APP[8-10]。其中最常见的突变基因为PSEN1,占 70%~80%[11],目前约有200多个PSEN1突变位点被报道(www.molgen.vib-ua.be/AD Mutations)oPSEN1蛋白是一种膜蛋白,它包含一个带有亲水基的细胞内环路的9次跨膜结构域。Psenl蛋白、Psen2蛋白、Nicastrin蛋白、APH-1及早老素增强子(PEN2)构成匕分泌酶复合体[12-13]。其中,nicastrin, APH-1与PSEN1蛋白C端结合,稳定该复合体[12]。而PEN2与PSEN1蛋白结合介导γ-分泌酶活性[14]。PSEN1突变导致γ-分泌酶活性改变,进而导致淀粉样前体蛋白清除异常,使Aβ42生成增多。 D198V突变发生在PSEN1基因7号外显子和PSEN1蛋白第4次跨膜结构域(TM4)上。D198V突变的病理性质是由高度保守的氨基酸决定的。到目前为止,该区域共有19个突变发生在202、206、209、212、213、 214、217、219密码子处(www.molgen.vib-ua.be/AD Mutations),表明TM4在功能上发挥着重要作用。PEN2 功能研究表明,PEN2嵌入到γ-分泌酶复合体上有赖于 PEN2与PSEN1蛋白的TM4结合[15]。突变的PSEN1蛋白上TM4的敲除会阻止PSEN1与PEN2的结合,随后活化诱导细胞死亡[15]。推测天冬氨酸转变为尽管携带致病基因的AD病例较为罕见,但是这些致病基因的发现有利于进一步了解AD发病的特点。结合该病例,我们发现相同位点的PSEN1突变具有临床异质性。之前我们课题组报道了6个PSEN1 突变,包括:A434T, S169del, L248P, F105C, I167del, L226R[16-17]。其中,S169del, L248P, F105C, L226R 临床特征为典型遗忘综合征,而A434T视幻觉和妄想早于记忆障碍3年出现;I167del记忆障碍出现3 年后伴有行为异常和痉挛性截瘫[16-17]。以上充分说明 PSEN1突变的AD患者临床表型具有异质性,这为早期AD诊断带来了一定困难,这也是AD被误诊为额颞叶痴呆或精神分裂症的重要原因。根据之前的报道, PSEN1 G209V、H163Y、R278I 突变的FAD患者易发生进行性非流利性失语症合并遗忘综合征,临床被误诊为额颞叶痴呆[18]。另外,同一家系中的患者携带同一PSEN1突变,临床表型也有差异:1)发病年龄:该家系先证者36岁起病,病情进展较快,而其他两位患者发病年龄较晚,病情进展较慢。2)首发症状:先证者首发症状为反应迟钝和近记忆力下降,而另外两个患者分别以精神异常和行为异常起病。3)临床特点:虽然三个患者在疾病进展过程中均出现了记忆力下降,但先证者伴有语言表达障碍,而另外两个患者语言功能受损不显著。最后结合分子诊断明确了该家系为早发家族性AD。该病例提示临床工作中遇到发病年龄早,非典型AD表现的患者在诊断时一定要谨慎,以免误诊。携带致病突变的家族性AD患者可能对多奈哌齐和美金刚的治疗效果不显著,这需要后期大样本来证实这一结论。
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