Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch R M, Gal A
Department of Human Genetics, University Hospital Eppendorf, University of Hamburg, Germany.
Am J Hum Genet. 2000 Jan;66(1):110-7. doi: 10.1086/302702.
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, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) 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.
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。在这两种疾病实体中，死后脑组织病理检查对于明确诊断至关重要。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。为了调查已知基因所致EOD的比例，我们对60岁以下EOD患者的基因组PCR产物进行测序，前瞻性地（即生前）筛查这四个基因的突变情况。16例患者痴呆家族史阳性（PFH），17例患者阴性（NFH），3例患者不明（UFH）。在12例患者中，我们发现了5个新突变（PS1中的F105L；PS2中的T122P和M239I；PrP中的Q160X和T188K）以及5个先前报道的突变（APP中的，3例极可能无亲缘关系患者中的V717I；PS1中的A79V和M139V；PrP中的P102L和T183A），这些均被认为是致病突变。在这12例患者中，9例有PFH。这表明PFH患者的检出率为56%（9/16）。我们在3例UFH患者中的2例中发现了2个突变（APP V717I），在17例NFH患者中的1例中仅发现1个突变（PrP T188K）。我们得出结论，由于缺乏FAD和遗传性朊病毒病的特异性生前诊断标志物，对于有PFH的EOD患者，所有四个基因都应纳入分子诊断程序。
