Wojtas Aleksandra, Heggeli Kristin A, Finch Nicole, Baker Matt, Dejesus-Hernandez Mariely, Younkin Steven G, Dickson Dennis W, Graff-Radford Neill R, Rademakers Rosa
Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16.
Alzheimer disease (AD) and frontotemporal dementia (FTD) are two frequent forms of primary neurodegenerative dementias with overlapping clinical symptoms. Pathogenic mutations of the amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) genes have been linked to familial early-onset forms of AD; however, more recently mutations in the common FTD genes encoding the microtubule associated protein tau (MAPT), progranulin (GRN) and C9ORF72, have also been reported in clinically diagnosed AD patients. To access the contribution of mutations in a well-characterized series of patients, we systematically performed genetic analyses of these EOAD and FTD genes in a novel cohort of 227 unrelated probands clinically diagnosed as probable AD which were ascertained at Mayo Clinic Florida between 1997 and 2011. All patients showed first symptoms of dementia before 70 years. We identified 9 different pathogenic mutations in the EOAD genes in a total of 11 patients explaining 4.8% of the patient population. Two mutations were novel: PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser. Importantly, mutations were also identified in all FTD genes: one patient carried a MAPT p.R406W mutation, one patient carried the p.Arg198Glyfs19X loss-of-function mutation in GRN and two patients were found to carry expanded GGGGCC repeats in the non-coding region of C9ORF72. Together the FTD genes explained the disease in 1.8% of our probable AD population. The identification of mutations in all major FTD genes in this novel cohort of clinically diagnosed AD patients underlines the challenges associated with the differential diagnosis of AD and FTD resulting from overlapping symptomatology and has important implications for molecular diagnostic testing and genetic counseling of clinically diagnosed AD patients. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include not only the well-established EOAD genes APP, PSEN1 and PSEN2 but also genes that are usually associated with FTD. Finally, the overall low frequency of mutation carriers observed in our study (6.6%) suggests the involvement of other as yet unknown genetic factors associated with AD.
阿尔茨海默病（AD）和额颞叶痴呆（FTD）是原发性神经退行性痴呆的两种常见形式，临床症状相互重叠。淀粉样前体蛋白（APP）以及早老素1和2（PSEN1、PSEN2）基因的致病性突变与家族性早发型AD相关；然而，最近在临床诊断为AD的患者中也报告了常见FTD基因的突变，这些基因编码微管相关蛋白tau（MAPT）、原纤维蛋白（GRN）和C9ORF72。为了评估一系列特征明确的患者中突变的作用，我们对227名无亲缘关系的先证者进行了这些早发型AD（EOAD）和FTD基因的系统遗传分析，这些先证者于1997年至2011年在佛罗里达州梅奥诊所被临床诊断为可能的AD。所有患者在70岁之前出现痴呆的首发症状。我们在总共11名患者的EOAD基因中鉴定出9种不同的致病性突变，占患者总数的4.8%。两种突变是新发现的：PSEN1 p.Pro218Leu和PSEN2 p.Phe183Ser。重要的是，在所有FTD基因中也发现了突变：一名患者携带MAPT p.R406W突变，一名患者携带GRN中的p.Arg198Glyfs19X功能丧失突变，两名患者在C9ORF72的非编码区发现有扩展的GGGGCC重复序列。FTD基因共同解释了我们可能患有AD的人群中1.8%的疾病。在这个临床诊断为AD的新队列中所有主要FTD基因中都发现了突变，这突出了由于症状重叠导致的AD和FTD鉴别诊断的挑战，并且对临床诊断为AD的患者的分子诊断检测和遗传咨询具有重要意义。我们的研究结果表明，在临床诊断为AD的患者中，遗传分析不仅应包括已确定的EOAD基因APP、PSEN1和PSEN2，还应包括通常与FTD相关的基因。最后，我们研究中观察到的突变携带者总体低频（6.6%）表明还存在其他与AD相关的未知遗传因素。
