Singleton A B, Hall R, Ballard C G, Perry R H, Xuereb J H, Rubinsztein D C, Tysoe C, Matthews P, Cordell B, Kumar-Singh S, De Jonghe C, Cruts M, van Broeckhoven C, Morris C M
Medical Research Council Neurochemical Pathology Unit, Institute for the Health of the Elderly and Department of Neuropathology, Newcastle General Hospital, Newcastle upon Tyne, UK.
Brain. 2000 Dec;123 Pt 12:2467-74. doi: 10.1093/brain/123.12.2467.
Most cases of familial presenile Alzheimer's disease are caused by mutations in the presenilin-1 (PSEN-1) gene, most of these mutations being missense mutations. A mutation in the splice donor site of intron 4 of PSEN-1 has been described recently which results in aberrant splicing of PSEN-1 mRNA, causing insertion of an additional amino acid, Thr113-114ins, into the protein. We studied the neuropathology of four cases bearing this mutation in an attempt to clarify the pathology of this hereditary form of Alzheimer's disease and to determine whether it differs from other familial forms of the disease. The disease presented as a progressive cognitive decline, myoclonus and seizures developing later in the disease, a feature common to PSEN-1-linked Alzheimer's disease. The course of the disease was relatively rapid, death occurring approximately 6 years after onset. Pathology in the intron 4 cases demonstrated a severe Alzheimer's disease pathology with abundant deposition of ss-amyloid (Ass) 1-42 senile plaques and the formation of neurofibrillary tangles. Amyloid angiopathy was present in these cases and was readily demonstrated by Ass 1-40 staining, particularly in the cerebellum. Cases with the intron 4 mutation appear clinically and pathologically similar to other cases of early-onset Alzheimer's disease bearing PSEN-1 mutations.
大多数家族性早老性阿尔茨海默病病例是由早老素-1（PSEN-1）基因突变引起的，其中大多数突变是错义突变。最近报道了PSEN-1基因第4内含子剪接供体位点的一种突变，该突变导致PSEN-1 mRNA异常剪接，致使蛋白质中额外插入一个氨基酸，即Thr113-114ins。我们研究了4例携带这种突变的病例的神经病理学，试图阐明这种遗传性阿尔茨海默病的病理学特征，并确定其是否与该疾病的其他家族形式有所不同。该疾病表现为进行性认知衰退，肌阵挛和癫痫在疾病后期出现，这是与PSEN-1相关的阿尔茨海默病的常见特征。疾病进程相对较快，发病后约6年死亡。第4内含子病例的病理学表现为严重的阿尔茨海默病病理学特征，有大量β-淀粉样蛋白（Aβ）1-42老年斑沉积和神经原纤维缠结形成。这些病例存在淀粉样血管病，通过Aβ 1-40染色很容易显示出来，尤其是在小脑中。具有第4内含子突变的病例在临床和病理上与其他携带PSEN-1突变的早发性阿尔茨海默病病例相似。
