PDF(Pubmed)
Abstract：
UNASSIGNED: Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary microgliopathy is a disorder where the pathogenic abnormality of the microglia causes white matter disorder and leads to a neuropsychiatric disease. Triggering receptor expressed on myeloid cells (TREM2), TYRO protein tyrosine kinase binding protein (TYROBP) and colony-stimulating factor 1 receptor (CSF1R) are genes implicated in primary microgliopathy. The clinical manifestations of primary microgliopathy are myriad ranging from neuropsychiatric syndrome, motor disability, gait dysfunction, ataxia, pure dementia, frontotemporal dementia (FTD), Alzheimer\'s dementia (AD), and so on. It becomes imperative to establish the diagnosis of microgliopathy masquerading as degenerative dementia, especially with promising therapies on horizon for the same. We aimed to describe a case series of subjects with dementia harbouring novel genes of primary microgliopathy, along with their clinical, neuropsychological, cognitive profile and radiological patterns.
UNASSIGNED: The prospective study was conducted in a university referral hospital in South India, as a part of an ongoing clinico-genetic research on dementia subjects, and was approved by the Institutional Ethics Committee. All patients underwent detailed assessment including sociodemographic profile, clinical and cognitive assessment, pedigree analysis and comprehensive neurological examination. Subjects consenting for blood sampling underwent genetic testing by whole-exome sequencing (WES).
UNASSIGNED: A total of 100 patients with dementia underwent genetic analysis using WES and three pathogenic variants, one each of TREM2, TYROBP, and CSF1R and two variants of uncertain significance in CSF1R were identified as cause of primary microgliopathy. TREM2 and TYROBP presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and as AD.
UNASSIGNED: WES has widened the spectrum of underlying neuropathology of degenerative dementias, and diagnosing primary microglial dysfunction with emerging therapeutic options is of paramount importance. The cases of primary microgliopathy due to novel mutations in TREM2, TYROBP, and CSF1R with the phenotype of degenerative dementia are being first time reported from Indian cohort. Our study enriches the spectrum of genetic variants implicated in degenerative dementia and provides the basis for exploring complex molecular mechanisms like microglial dysfunction, as underlying cause for neurodegeneration.
UNASSIGNED: The prospective study was conducted in a university referral hospital in South India, as a part of an ongoing clinico-genetic research on dementia subjects, and was approved by the Institutional Ethics Committee. All patients underwent detailed assessment including sociodemographic profile, clinical and cognitive assessment, pedigree analysis and comprehensive neurological examination. Subjects consenting for blood sampling underwent genetic testing by whole-exome sequencing (WES).
UNASSIGNED: A total of 100 patients with dementia underwent genetic analysis using WES and three pathogenic variants, one each of TREM2, TYROBP, and CSF1R and two variants of uncertain significance in CSF1R were identified as cause of primary microgliopathy. TREM2 and TYROBP presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and as AD.
UNASSIGNED: WES has widened the spectrum of underlying neuropathology of degenerative dementias, and diagnosing primary microglial dysfunction with emerging therapeutic options is of paramount importance. The cases of primary microgliopathy due to novel mutations in TREM2, TYROBP, and CSF1R with the phenotype of degenerative dementia are being first time reported from Indian cohort. Our study enriches the spectrum of genetic variants implicated in degenerative dementia and provides the basis for exploring complex molecular mechanisms like microglial dysfunction, as underlying cause for neurodegeneration.
摘要：
■小胶质细胞在白质完整性的稳态中发挥关键作用，一些研究强调了小胶质细胞功能障碍在神经变性中的作用。原发性小胶质细胞病是小胶质细胞的致病异常引起白质障碍并导致神经精神疾病的病症。在骨髓细胞上表达的触发受体（TREM2），TYRO蛋白酪氨酸激酶结合蛋白（TYROBP）和集落刺激因子1受体（CSF1R）是与原发性小胶质细胞病有关的基因。原发性小胶质细胞病的临床表现多种多样，包括神经精神综合征，运动障碍,步态功能障碍,共济失调,纯粹的痴呆,额颞叶痴呆(FTD),老年痴呆症(AD),等等。建立伪装成退行性痴呆的小胶质细胞病的诊断势在必行，尤其是有希望的治疗方法。我们旨在描述一系列患有痴呆的受试者，这些受试者具有原发性小胶质细胞病的新基因，随着他们的临床，神经心理学，认知概况和放射学模式。
■这项前瞻性研究是在印度南部的一所大学转诊医院进行的，作为正在进行的痴呆症患者临床遗传学研究的一部分，并获得机构伦理委员会的批准。所有患者都接受了详细的评估，包括社会人口统计学特征，临床和认知评估，家系分析和全面的神经系统检查。同意采血的受试者通过全外显子组测序(WES)进行基因检测。
■共有100名痴呆症患者使用WES和三种致病变异进行了遗传分析，TREM2，TYROBP，CSF1R和CSF1R中两个意义不确定的变异体被确定为原发性小胶质细胞病的病因。TREM2和TYROBP表现为额颞叶综合征，而CSF1R表现为额颞叶综合征和AD。
■WES扩大了退行性痴呆的潜在神经病理学的范围，新出现的治疗方案诊断原发性小胶质细胞功能障碍至关重要.由于TREM2，TYROBP，以及CSF1R与退行性痴呆表型的首次报道来自印度队列。我们的研究丰富了与退行性痴呆有关的遗传变异谱，并为探索小胶质细胞功能障碍等复杂的分子机制提供了基础。作为神经变性的根本原因。
■这项前瞻性研究是在印度南部的一所大学转诊医院进行的，作为正在进行的痴呆症患者临床遗传学研究的一部分，并获得机构伦理委员会的批准。所有患者都接受了详细的评估，包括社会人口统计学特征，临床和认知评估，家系分析和全面的神经系统检查。同意采血的受试者通过全外显子组测序(WES)进行基因检测。
■共有100名痴呆症患者使用WES和三种致病变异进行了遗传分析，TREM2，TYROBP，CSF1R和CSF1R中两个意义不确定的变异体被确定为原发性小胶质细胞病的病因。TREM2和TYROBP表现为额颞叶综合征，而CSF1R表现为额颞叶综合征和AD。
■WES扩大了退行性痴呆的潜在神经病理学的范围，新出现的治疗方案诊断原发性小胶质细胞功能障碍至关重要.由于TREM2，TYROBP，以及CSF1R与退行性痴呆表型的首次报道来自印度队列。我们的研究丰富了与退行性痴呆有关的遗传变异谱，并为探索小胶质细胞功能障碍等复杂的分子机制提供了基础。作为神经变性的根本原因。
