Bourbouli Mara, Paraskevas George P, Rentzos Mihail, Mathioudakis Lambros, Zouvelou Vasiliki, Bougea Anastasia, Tychalas Athanasios, Kimiskidis Vasilios K, Constantinides Vasilios, Zafeiris Spiros, Tzagournissakis Minas, Papadimas Georgios, Karadima Georgia, Koutsis Georgios, Kroupis Christos, Kartanou Chrisoula, Kapaki Elisabeth, Zaganas Ioannis
Neurogenetics Laboratory, Neurology Department, Medical School, University of Crete, 71003 Heraklion, Greece.
1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, Greece.
Brain Sci. 2021 Sep 19;11(9):1239. doi: 10.3390/brainsci11091239.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and FTD-ALS, to measure levels of CSF biomarkers and to investigate genotype-phenotype/CSF biomarker associations. In this cohort of 130 patients (56 FTD, 58 ALS and 16 FTD-ALS), we performed hexanucleotide repeat expansion analysis, whole exome sequencing and measurement of "classical" (Aβ, total tau and phospho-tau) and novel (TDP-43) CSF biomarkers and plasma progranulin. Through these analyses, we identified 14 patients with repeat expansion and 11 patients with causative variants in other genes (three in , three in , three in , one in , one in ). In ALS patients, we found that levels of phospho-tau were lower in repeat expansion and c.855C>T (p.Asp285Asp) carriers compared to non-carriers. Additionally, carriers of rare and variants had lower levels of total tau and Aβ, respectively. Plasma progranulin levels were decreased in patients carrying pathogenic variants. This study expands the genotypic and phenotypic spectrum of FTD/ALS and offers insights in possible genotypic/CSF biomarker associations.
额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）属于同一病理生理谱，具有共同的遗传和脑脊液（CSF）生物标志物。我们此次的目的是在一组希腊FTD、ALS和FTD-ALS患者中鉴定致病基因变异，测量CSF生物标志物水平，并研究基因型-表型/CSF生物标志物关联。在这组130名患者（56例FTD、58例ALS和16例FTD-ALS）中，我们进行了六核苷酸重复扩增分析、全外显子组测序，并测量了“经典”（Aβ、总tau蛋白和磷酸化tau蛋白）和新型（TDP-43）CSF生物标志物以及血浆原颗粒蛋白。通过这些分析，我们鉴定出14例有重复扩增的患者和11例在其他基因中有致病变异的患者（3例在[基因名称未给出]，3例在[基因名称未给出]，3例在[基因名称未给出]，1例在[基因名称未给出]，1例在[基因名称未给出]）。在ALS患者中，我们发现与非携带者相比，六核苷酸重复扩增和c.855C>T（p.Asp285Asp）携带者的磷酸化tau蛋白水平较低。此外，罕见[基因名称未给出]和[基因名称未给出]变异的携带者分别具有较低的总tau蛋白和Aβ水平。携带[基因名称未给出]致病变异的患者血浆原颗粒蛋白水平降低。本研究扩展了FTD/ALS的基因型和表型谱，并为可能的基因型/CSF生物标志物关联提供了见解。
