United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Camberwell, London, UK.
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Neurobiol Aging. 2019 Jan;73:229.e5-229.e9. doi: 10.1016/j.neurobiolaging.2018.08.015. Epub 2018 Aug 24.
Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p = 0.0026).
对 226 例英国家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆的外显子组测序分析发现，分别有 2 例个体携带 P497H 和 P506S UBQLN2 突变（n=0.9%）。P506S 指数病例 54 岁时表现为行为变异型额颞叶痴呆，随后进展为 ALS，存活 3 年。3 个儿子分别表现为（1）25 岁发病的缓慢进展性纯痉挛性截瘫，（2）25 岁发病的 ALS 并存活 2 年，以及（3）26 岁发病的 ALS。对指数病例的尸检组织分析显示，齿状回中神经元细胞质 UBQLN2 阳性包涵体频繁，额颞叶皮质和海马齿状回颗粒细胞层中 TDP-43 阳性神经元细胞质包涵体。此外，对已发表的 UBQLN2 突变的综合分析表明，只有富含脯氨酸的结构域突变会导致男性患者的发病年龄明显提前（p=0.0026）。
