Cornish Kim M, Li Lexin, Kogan Cary S, Jacquemont Sebastien, Turk Jeremy, Dalton Ann, Hagerman Randi J, Hagerman Paul J
Neuroscience Laboratory for Research and Education in Developmental Disorders, McGill University, Montreal, Canada.
Cortex. 2008 Jun;44(6):628-36. doi: 10.1016/j.cortex.2006.11.002. Epub 2007 Dec 23.
Fragile X syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the fragile X mental retardation 1 (FMR1) gene. Affected individuals display a unique neurocognitive phenotype that includes significant impairment in inhibitory control, selective attention, working memory, and visual-spatial cognition. In contrast, little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (i.e., "carrier status") or its relationship with the recently identified neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). In the present study, we evaluated a broad sample of 40 premutation males (PM) aged 18-69 years matched on age and IQ to 67 unaffected comparison males (NC). Performance was compared across a range of cognitive domains known to be impaired in fragile X syndrome (i.e., "full mutation"). Tremor was also assessed using a self-report neurological questionnaire. PM displayed statistically significant deficits in their ability to inhibit prepotent responses, differentiating them from NC from age 30 onwards. With increasing age, the two groups follow different trajectories, with PM developing progressively more severe problems in inhibitory control. This deficit also has a strong co-occurrence in males displaying FXTAS-related symptomatology (p<.001). Selective attention was also impaired in PM but did not show any disproportionate aging effect. No other cognitive deficits were observed. We conclude that an inhibitory deficit and its impact across the lifespan are specifically associated with the fragile X premutation status, and may be a precursor for development of a more severe form of cognitive impairment or dementia, which has been reported in patients with the diagnosis of FXTAS.
脆性X综合征是一种神经发育障碍，由X染色体上的一个单基因——脆性X智力低下1（FMR1）基因沉默所致。受影响个体表现出独特的神经认知表型，包括抑制控制、选择性注意、工作记忆和视觉空间认知方面的显著损害。相比之下，对于与脆性X前突变（即“携带者状态”）相关的任何认知障碍的轨迹和特异性，或者其与最近发现的神经退行性疾病——脆性X相关震颤/共济失调综合征（FXTAS）的关系，人们了解甚少。在本研究中，我们评估了40名年龄在18至69岁之间的前突变男性（PM）的广泛样本，这些男性在年龄和智商方面与67名未受影响的对照男性（NC）相匹配。在一系列已知在脆性X综合征（即“全突变”）中受损的认知领域中比较了表现。还使用一份自我报告的神经学问卷评估了震颤情况。从30岁起，PM在抑制优势反应的能力上表现出统计学上的显著缺陷，这使他们与NC有所不同。随着年龄的增长，两组遵循不同的轨迹，PM在抑制控制方面出现越来越严重的问题。这种缺陷在表现出FXTAS相关症状的男性中也有很强的共现性（p<0.001）。PM的选择性注意也受损，但未显示出任何不成比例的衰老效应。未观察到其他认知缺陷。我们得出结论，抑制缺陷及其对整个生命周期的影响与脆性X前突变状态特别相关，并且可能是发展为更严重形式的认知障碍或痴呆的先兆，这在被诊断为FXTAS的患者中已有报道。
