探索肌萎缩侧索硬化症中膜联蛋白A11变体的表型特征：一项基于欧洲队列的人群研究。

Exploring the phenotypic fingerprints of ANXA11 variants in ALS: a population-based study in an European cohort.

作者信息

Palumbo Francesca, Iazzolino Barbara, Moglia Cristina, Manera Umberto, Matteoni Enrico, Cabras Sara, Brunetti Maura, Gallone Salvatore, Callegaro Stefano, Vasta Rosario, Mora Gabriele, De Marchi Fabiola, Corrado Lucia, D'Alfonso Sandra, Mazzini Letizia, Canosa Antonio, Grassano Maurizio, Calvo Andrea, Chiò Adriano

机构信息

ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Via Cherasco 15, 10126, Turin, Italy.

Neurology 1, Azienda Ospedaliero-Universitaria Città Della Salute E Della Scienza of Torino, Turin, Italy.

出版信息

J Neurol. 2025 Jul 21;272(8):524. doi: 10.1007/s00415-025-13276-w.

DOI:10.1007/s00415-025-13276-w

PMID:40690048

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12279584/

Abstract

BACKGROUND

Annexin A11 (ANXA11) has emerged as a significant gene associated with amyotrophic lateral sclerosis (ALS) and cognitive impairments. This study aimed to evaluate the prevalence and clinical and cognitive features of pathogenic variants in ANXA11 in an Italian ALS cohort.

METHODS

Data were collected from the Piemonte and Valle d'Aosta Register for ALS between 2009 and 2020. Only patients who underwent whole genome sequencing (WGS) were included. Clinical and cognitive assessments were compared among patients with ANXA11-ALS, wild-type ALS (WT-ALS), and C9ORF72-ALS.

RESULTS

Among 1,486 ALS patients, 18 (1.4%) were found to carry ANXA11 variants, four of which were classified as benign or likely benign. Three patients (16.7%) also had co-occurring variants in ERBB4 (erb-b2 receptor tyrosine kinase 4), EPHA4 (ephrin type-A receptor 4), or C9ORF72 (chromosome 9 open reading frame 72). Patients with ANXA11-ALS had significantly lower education levels (6.2 vs. 8.9 years), higher BMI at diagnosis (26.7 vs. 24.5), and a higher prevalence of cognitive impairment (100% vs. 47%) compared to WT-ALS. Cognitive testing revealed more severe deficits in executive function, attention, psychomotor speed, non-verbal intelligence, and cognitive flexibility, though no behavioral differences were observed. Compared to C9ORF72-ALS, ANXA11-ALS patients were older at diagnosis (66.6 vs. 60.3 years), had lower education levels (6.2 vs. 9.0 years), and higher rates of cognitive impairment (100% vs. 68.7%).

DISCUSSION

Pathogenic ANXA11 variants are relatively common in ALS and are strongly associated with cognitive impairment. Including ANXA11 in routine genetic screening may enhance diagnostic precision and therapeutic strategies for ALS patients.

摘要

背景

膜联蛋白A11（ANXA11）已成为与肌萎缩侧索硬化症（ALS）和认知障碍相关的重要基因。本研究旨在评估意大利ALS队列中ANXA11致病变异的患病率、临床和认知特征。

方法

收集了2009年至2020年间皮埃蒙特和瓦莱达奥斯塔ALS登记处的数据。仅纳入接受全基因组测序（WGS）的患者。对ANXA11-ALS患者、野生型ALS（WT-ALS）患者和C9ORF72-ALS患者进行了临床和认知评估并比较。

结果

在1486例ALS患者中，发现18例（1.4%）携带ANXA11变异，其中4例被分类为良性或可能良性。3例患者（16.7%）在ERBB4（erb-b2受体酪氨酸激酶4）、EPHA4（Ephrin A型受体4）或C9ORF72（9号染色体开放阅读框72）中也存在共发变异。与WT-ALS相比，ANXA11-ALS患者的教育水平显著较低（6.2年对8.9年），诊断时的BMI较高（26.7对24.5），认知障碍患病率较高（100%对47%）。认知测试显示，尽管未观察到行为差异，但执行功能、注意力、精神运动速度、非语言智力和认知灵活性方面的缺陷更为严重。与C9ORF72-ALS相比，ANXA11-ALS患者诊断时年龄更大（66.6岁对60.3岁），教育水平更低（6.2年对9.0年），认知障碍发生率更高（100%对68.7%）。