<i>CSF1R</i>-related leukoencephalopathy: A major player in primary microgliopathies.

Abstract

Since the discovery of <i>CSF1R</i> gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, <i>CSF1R</i>-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of <i>Csf1r</i> haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with <i>CSF1R</i> mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which <i>CSF1R</i> mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, <i>CSF1R</i>-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of <i>CSF1R</i>-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.