Primary Microgliopathy Presenting as Degenerative Dementias: A Case Series of Novel Gene Mutations from India.

Autor:	Ramakrishnan S; Department of Neurology, National Institute of Mental Health, and Neurosciences (NIMHANS), Bengaluru, India., Arshad F; Department of Neurology, National Institute of Mental Health, and Neurosciences (NIMHANS), Bengaluru, India., Bs K; Department of Neurology, National Institute of Mental Health, and Neurosciences (NIMHANS), Bengaluru, India., Pon AG; Department of Neurology, National Institute of Mental Health, and Neurosciences (NIMHANS), Bengaluru, India., Bosco S; Department of Human Genetics, NIMHANS, Bengaluru, India., Kumar S; Department of Neurology, National Institute of Mental Health, and Neurosciences (NIMHANS), Bengaluru, India., Chidambaram H; Department of Neurochemistry, NIMHANS, Bengaluru, India., Chinnathambi SCB; Department of Neurochemistry, NIMHANS, Bengaluru, India., Kulanthaivelu K; Department of Neuroimaging and Interventional Radiology, NIMHANS, Bengaluru, India., Arunachal G; Department of Human Genetics, NIMHANS, Bengaluru, India., Alladi S; Department of Neurology, National Institute of Mental Health, and Neurosciences (NIMHANS), Bengaluru, India.
Jazyk:	angličtina
Zdroj:	Dementia and geriatric cognitive disorders extra [Dement Geriatr Cogn Dis Extra] 2024 Mar 08; Vol. 14 (1), pp. 14-28. Date of Electronic Publication: 2024 Mar 08 (Print Publication: 2024).
DOI:	10.1159/000538145
Abstrakt:	Introduction: 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. Methods: 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). Results: 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. Conclusion: 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (© 2024 The Author(s). Published by S. Karger AG, Basel.)
Databáze:	MEDLINE
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