Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series
Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series
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DOI：
10.1016/s1474-4422(16)30193-4
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发表时间：
2016-12-01
期刊：
影响因子：
48
通讯作者：
Fox, Nick C.
中科院分区：
文献类型：
--
作者：
Ryan, Natalie S.;Nicholas, Jennifer M.;Fox, Nick C.
背景常染色体显性遗传的家族性阿尔茨海默病表型异质性的原因尚不清楚。我们的目的是阐明症状性常染色体显性遗传家族性阿尔茨海默病（ADAD）的临床表型和与APP和PSEN1突变的遗传相关性。（症状出现时的年龄、最初的认知或行为症状以及是否存在肌齿、癫痫发作、锥体束征、锥体外系征，和小脑体征），来自于英国伦敦痴呆症研究中心发现的APP或PSEN1突变导致的ADAD患者。我们检查了出现症状的频率和其他神经功能特征，调查了症状发作时年龄，APOE基因型和突变位置的相关性，并探讨了APP和PSEN1突变携带者之间的表型差异。采用描述性统计方法，按突变类型分层，对出现各种症状的个体比例进行分析。结果1987年7月1日至2015年10月31日，记录了213例患者的发病年龄（168例PSEN1突变和45例APP突变），121例患者（85例PSEN1突变，36例APP突变）有详细的病史和神经系统检查结果。我们鉴定了38种不同的PSEN1突变（4种新的）和6种APP突变（1种新的）。发病年龄因突变而异，PSEN1突变个体比APP突变个体发病年龄更小（平均年龄分别为43.6岁[SD 7.2] vs 50.4岁[SD 5.2]，p
Background The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD).Methods We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myodonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type.Findings Between July 1,1987, and Oct 31,2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43.6 years [SD 7.2] vs 50.4 years [SD 5.2], respectively, p