Figure 5. Microglia-oriented hypothesis for colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy.

Based on the haploinsufficiency or loss of function of mutant CSF1R, it is thought that microglia possess a half amount of functional CSF1R in patients with CSF1R-related leukoencephalopathy. This may influence not only microglial physiologic function in adult brains, but also microglial development in fetal brains since embryonic microglial development and maturation are dependent on CSF1R. Therefore, the character of microglia in patients may be somewhat different from individuals with a full amount of functional CSF1R, even at the time of birth. In adult brains, aberrant microglia may have a pivotal role in the white matter degeneration, which is characterized by primary axonopathy (spheroid formation shown in brown) and following demyelination (shown as dot lines surrounding the neuronal axon). Ballooned neurons are frequently found in the overlying cortex. Given that patients develop clinical symptom in adult, a half amount of functional CSF1R is considered to be sufficient for surviving to adulthood; however, white matter degeneration and corpus callosum atrophy could precede symptom onset. Importantly, brain calcification can be observed at birth, implying that the calcifications are independent of white matter degeneration or clinical symptoms.