Rippon Gregory A, Crook Richard, Baker Matthew, Halvorsen Elizabeth, Chin Steven, Hutton Michael, Houlden Henry, Hardy John, Lynch Timothy
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Arch Neurol. 2003 Jun;60(6):884-8. doi: 10.1001/archneur.60.6.884.
Alzheimer disease (AD) is characterized by memory and visuospatial deficits with relative sparing of personality. Mutations in 3 genes (presenilin 1 and 2 and amyloid precursor protein) are associated with presenile AD. Presenilin 1 gene mutations have not been described in African Americans.
We studied an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade of life. We performed neurologic evaluations, psychometrics, and neuroimaging. We sequenced the amyloid precursor protein gene, presenilin 1 and 2, and tau in affected and unaffected family members. One patient underwent a brain biopsy and subsequent autopsy.
Personality change, auditory and visual hallucinations, delusions, memory impairment, word-finding difficulties, and subsequent rigidity, dystonia, myoclonus, and mutism developed in 2 brothers. Neuropsychometric testing in one was consistent with frontotemporal dementia or atypical AD. Neuroimaging studies showed diffuse cortical involvement. A clinical diagnosis of familial non-Alzheimer dementia was made. However, results of temporal lobe biopsy in one revealed amyloid neuritic plaques, and autopsy results confirmed the diagnosis of AD. Gene sequencing revealed a presenilin 1 point mutation (M139V) cosegregating with the disease. A tau polymorphism in exon 7 (A178T) was found in an affected brother and unaffected relatives.
We report the first documented presenilin mutation in African American patients presenting with early personality change, psychosis, and memory loss with preserved praxis. The M139V mutation can present differently between kindreds, with some features suggestive of a frontal lobe syndrome. The M139V mutation can lead to atypical AD, and genetic background may have a role in determining the phenotype of genetically defined AD.
阿尔茨海默病（AD）的特征是记忆和视觉空间功能缺陷，而人格相对保留。3个基因（早老素1和2以及淀粉样前体蛋白）的突变与早老性AD相关。早老素1基因突变在非裔美国人中尚未见报道。
我们研究了一个非裔美国家庭，该家庭患有常染色体显性快速进展性痴呆和在生命第五个十年早期出现的精神病。我们进行了神经学评估、心理测量和神经影像学检查。我们对患病和未患病的家庭成员的淀粉样前体蛋白基因、早老素1和2以及tau进行了测序。一名患者接受了脑活检及随后的尸检。
2名兄弟出现了人格改变、听觉和视觉幻觉、妄想、记忆障碍、找词困难，随后出现僵硬、肌张力障碍、肌阵挛和缄默。其中一人的神经心理测试结果与额颞叶痴呆或非典型AD相符。神经影像学研究显示弥漫性皮质受累。临床诊断为家族性非阿尔茨海默痴呆。然而，其中一人的颞叶活检结果显示有淀粉样神经炎斑块，尸检结果证实为AD诊断。基因测序显示一个早老素1点突变（M139V）与疾病共分离。在一名患病兄弟和未患病亲属中发现了外显子7中的tau多态性（A178T）。
我们报告了首例有记录的非裔美国患者早老素突变，这些患者表现为早期人格改变、精神病和记忆丧失且动作能力保留。M139V突变在不同家族中可能有不同表现，有些特征提示额叶综合征。M139V突变可导致非典型AD，遗传背景可能在决定基因定义的AD表型中起作用。
