Data from: CSF1R-related leukoencephalopathy: a major player in primary microgliopathies

Since the discovery of CSF1R 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, CSF1R-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 Csf1r haploinsufficient mouse model. These mice develop
clinical, radiologic, and pathologic phenotypes consistent with those of
human patients with CSF1R mutations. In vitro, perturbation of CSF1R
signaling is shown in cultured cells expressing mutant CSF1R. However, the
underlying mechanisms by which CSF1R mutations selectively lead to white
matter degeneration remains to be elucidated. Given that CSF1R mainly
expresses in microglia, CSF1R-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 CSF1R-related leukoencephalopathy and discuss the
putative pathophysiology, with a focus on microglia, as well as future
research directions.