Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Università degli Studi di Milano, P.le Brescia 20, 20149, Milan, Italy.
"Dino Ferrari Center", Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122, Milan, Italy.
J Neurol. 2023 Feb;270(2):898-908. doi: 10.1007/s00415-022-11433-z. Epub 2022 Oct 29.
Amyotrophic lateral sclerosis (ALS) individuals carrying the hexanucleotide repeat expansion (HRE) in the C9orf72 gene (C9Pos) have been described as presenting distinct features compared to the general ALS population (C9Neg). We aim to identify the phenotypic traits more closely associated with the HRE and analyse the role of the repeat length as a modifier factor.
We studied a cohort of 960 ALS patients (101 familial and 859 sporadic cases). Motor phenotype was determined using the MRC scale, the lower motor neuron score (LMNS) and the Penn upper motor neuron score (PUMNS). Neuropsychological profile was studied using the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Frontal Behavioral Inventory (FBI), the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI). A two-step PCR protocol and Southern blotting were performed to determine the presence and the size of C9orf72 HRE, respectively.
C9orf72 HRE was detected in 55/960 ALS patients. C9Pos patients showed a younger onset, higher odds of bulbar onset, increased burden of UMN signs, reduced survival and higher frequency of concurrent dementia. We found an inverse correlation between the HRE length and the performance at ECAS ALS-specific tasks (P = 0.031). Patients also showed higher burden of behavioural disinhibition (P = 1.6 × 10), lower degrees of depression (P = 0.015) and anxiety (P = 0.008) compared to C9Neg cases.
Our study provides an extensive characterization of motor, cognitive and behavioural features of C9orf72-related ALS, indicating that the C9orf72 HRE size may represent a modifier of the cognitive phenotype.
携带 C9orf72 基因六核苷酸重复扩展（HRE）的肌萎缩侧索硬化症（ALS）患者与一般 ALS 人群（C9Neg）相比，表现出明显不同的特征。我们旨在确定与 HRE 更密切相关的表型特征，并分析重复长度作为修饰因子的作用。
我们研究了 960 名 ALS 患者（101 例家族性和 859 例散发性病例）的队列。使用 MRC 量表、下运动神经元评分（LMNS）和宾夕法尼亚上运动神经元评分（PUMNS）来确定运动表型。使用意大利版爱丁堡认知和行为 ALS 筛查（ECAS）、额叶行为量表（FBI）、贝克抑郁量表 II（BDI-II）和状态特质焦虑量表（STAI）研究神经心理学特征。使用两步 PCR 方案和 Southern 印迹分别检测 C9orf72 HRE 的存在和大小。
在 960 名 ALS 患者中检测到 55 例 C9orf72 HRE。C9Pos 患者发病年龄较早，球部起病率较高，上运动神经元体征负担较重，生存率降低，并发痴呆症的频率较高。我们发现 HRE 长度与 ECAS ALS 特异性任务的表现呈负相关（P=0.031）。与 C9Neg 病例相比，患者还表现出更高的行为抑制障碍负担（P=1.6×10）、更低程度的抑郁（P=0.015）和焦虑（P=0.008）。
我们的研究提供了 C9orf72 相关 ALS 的运动、认知和行为特征的广泛特征，表明 C9orf72 HRE 大小可能是认知表型的修饰因子。
