Barbier Mathieu, Wallon David, Le Ber Isabelle
Inserm U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université, Institut du cerveau et de la moelle épinière, Paris, France, Unité de recherche clinique, Hôpital de la Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, France.
Département de neurologie et CNR-MAJ, CHU de Rouen, Rouen, France ; Inserm U1245, Unirouen, Normandie université, Rouen, France.
Geriatr Psychol Neuropsychiatr Vieil. 2018 Sep 1;16(3):289-297. doi: 10.1684/pnv.2018.0744.
Early-onset Alzheimer's disease (EOAD) and frontotemporal lobar dementia (FTLD) account for the majority of early-onset dementia (onset before 65 years). The high frequency of genetic forms is a common feature of EOAD and FTLD. A lot of efforts have been done to unravel the genetic bases of monogenic forms of these two diseases. PSEN1, APP and PSEN2 are the major causes of monogenic EOAD while GRN, MAPT and C9ORF72 are the most frequently mutated genes in familial FTLD. Besides, the rise of new generation sequencing technologies (NGS) during the last decade allowed a better description of the genetic architecture. A myriad of genes implicated each in a lower number of families with variable penetrance have been highlighted, especially in FTLD. The genetic heterogeneity and it contribution to the clinical variability have been described with more detailed and the process of molecular diagnostic has been modified as well. Here we propose to review old and recent findings about the contribution of genetic factors into these two major early-onset dementia diseases. The impact on the diagnostic and on the knowledge of associated pathophysiological mechanisms is also discussed.
早发性阿尔茨海默病（EOAD）和额颞叶痴呆（FTLD）占早发性痴呆（65岁之前发病）的大部分。遗传形式的高发生率是EOAD和FTLD的共同特征。人们已经做了很多努力来揭示这两种疾病单基因形式的遗传基础。PSEN1、APP和PSEN2是单基因EOAD的主要病因，而GRN、MAPT和C9ORF72是家族性FTLD中最常发生突变的基因。此外，过去十年新一代测序技术（NGS）的兴起使得对遗传结构有了更好的描述。大量基因被发现，每个基因在较少数量的具有可变外显率的家族中起作用，尤其是在FTLD中。遗传异质性及其对临床变异性的影响已得到更详细的描述，分子诊断过程也已得到改进。在此，我们建议回顾关于遗传因素对这两种主要早发性痴呆疾病贡献的新旧发现。还讨论了其对诊断以及相关病理生理机制认识的影响。
