Costello Emmet, Ryan Marie, Donohoe Bronagh, Kavanagh Caoimhe, Pinto-Grau Marta, Doherty Mark, McLaughlin Russell Lewis, McHutchison Caroline, Abrahams Sharon, Heverin Mark, Hardiman Orla, Pender Niall
Academic Unit of Neurology, Trinity Biomedical Science Institute, Dublin D02 R590, Ireland.
Psychology Department, Beaumont Hospital, Dublin D09 V2N0, Ireland.
Brain Commun. 2023 May 19;5(3):fcad166. doi: 10.1093/braincomms/fcad166. eCollection 2023.
First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis ( = 149) were compared to controls ( = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and repeat expansion status ( = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming ( = 0.91, = 0.00001) and phonemic verbal fluency ( = 0.81, = 0.0003). Relatives also had higher autism quotient attention to detail traits ( = -0.52, = 0.005), lower conscientiousness ( = 0.57, = 0.003) and lower openness to experience personality traits ( = 0.54, = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the expansion.
肌萎缩侧索硬化症患者的一级和二级亲属报告的神经精神疾病发病率较高，这表明风险基因可能具有多效性，在家族中导致多种表型。这些表型可能构成一种与疾病易感性相关的疾病内表型。我们直接研究了肌萎缩侧索硬化症患者亲属的认知功能和神经精神特征，以确定该疾病潜在的内表型。在一项基于家庭的横断面研究设计中，使用深入的神经心理学和神经精神评估，将肌萎缩侧索硬化症患者的一级和二级亲属（n = 149）与对照组（n = 60）进行比较。亚组分析检查了家族史和C9orf72重复扩增状态（n = 16名阳性携带者）的影响。与对照组相比，肌萎缩侧索硬化症患者的亲属在执行功能、语言和记忆任务上得分较低，在物体命名（d = 0.91，p = 0.00001）和音素言语流畅性（d = 0.81，p = 0.0003）方面观察到较大的效应量。亲属在自闭症商数注重细节特质方面也高于对照组（d = -0.52，p = 0.005），在尽责性方面低于对照组（d = 0.57，p = 0.003），在开放性经验人格特质方面低于对照组（d = 0.54，p = 0.01）。这些效应在家族性而非散发性肌萎缩侧索硬化症患者的亲属中通常更大，并且在先证者C9orf72重复扩增的基因携带者和非携带者亲属中均存在。音素流畅性和物体命名较差，以及自闭症和人格特质，在肌萎缩侧索硬化症患者的亲属中更为常见。在携带C9orf72重复扩增的家族中，无论亲属的携带者状态如何，这些特质都在亲属中被发现，这表明存在一种与疾病相关的内表型，其并非完全由C9orf72扩增介导。
