High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes
High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes
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DOI：
10.1086/302702
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发表时间：
2000-01-01
影响因子：
9.8
通讯作者：
Gal, A
中科院分区：
文献类型：
--
作者：
Finckh, U;Müller-Thomsen, T;Gal, A
早发性痴呆（EOD）的临床鉴别诊断包括家族性阿尔茨海默病（FAD）和遗传性朊病毒病。在这两种疾病的实体，死后脑组织病理学检查是必不可少的明确诊断。编码早老素（PS1和PS2）和淀粉样前体蛋白（APP）的基因突变与FAD相关，而朊病毒蛋白（PrP）基因突变与朊病毒病相关。为了调查归因于已知基因的EOD的比例，我们前瞻性地（即，通过对60岁之前患有EOD的患者的基因组PCR产物进行测序来筛选这四个基因的突变。痴呆家族史阳性（PFH）16例，阴性（NFH）17例，未知（UFH）3例。在12名患者中，我们发现了5种新型突变（PS1、F105 L; PS2、T122 P和M239 I;以及PrP、Q160 X和T188 K）和5种之前报道的突变（APP，在三名最有可能不相关的患者中，V7171; PS1、A79 V和M139 V;以及PrP、P102 L和T183 A），这些突变都被认为是致病的。在这12例患者中，3例患有PFH。这表明PFH患者的检出率为56%（3/16）。我们在3例UFH患者中的2例中发现了两个突变（APP V717 I），在17例NFH患者中的1例中仅发现了一个突变（PrP T188 K）。我们的结论是，由于缺乏特定的死前诊断标志物FAD和遗传性朊病毒病，所有四个基因应包括在一个分子诊断程序的EOD患者PFH。
Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V7171; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 3 had PFH. This indicates a detection rate of 56% (3/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.