Abstract
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1+ clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.