Primary microgliopathy presenting as degenerative dementias: A case series of novel gene mutations from India

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 are disorders where the pathogenic abnormality of the microglia causes white matter disorder and leads to a neuropsychiatric diseases. Triggering Receptor Expressed on Myeloid Cells (TREM2), TYRO protein tyrosine kinase binding protein (TYROBP), Colony-stimulating factor 1 receptor (CSF1R) are genes implicated in primary microgliopathy. Clinical manifestations of primary microgliopathy are myriad ranging from neuropsychiatric syndrome, motor disability, gait dysfunction, ataxia, pure dementia, frontotemporal dementia, Alzheimer dementia and so on. It becomes imperative to establish diagnosis of microgliopathy masquerading as degenerative dementia, especially with promising therapies on horizon for the same. We aim to describe a case series of subjects with dementia harboring novel genes of primary microgliopathy, along with their clinical, neuropsychological, and 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 clinic-genetic research on Dementia subjects and was approved by the institutional ethics committee. All patients underwent detailed assessment including socio demographic 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: 100 patients of dementia underwent genetic analysis using whole exome sequencing 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 .TREM 2 and TYROBP presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and Alzheimer dementia. 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. Cases of primary microgliopathy due to Novel mutations in TREM2, TYROBP and CSF1R with 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