| Frameshift and nonsense mutations | Result in truncated, non-functional proteins, typically causing haploinsufficiency. |
| Splice-site mutations | Disrupt normal mRNA processing. |
| PI3K/AKT pathway | Promotes microglial survival and anti-inflammatory functions. |
| MAPK/ERK pathway | Regulates proliferation and differentiation. |
| PLCγ signaling | Mediates calcium-dependent cellular functions. |
| TREM2 interactions | CSF1R and TREM2 share downstream signaling pathways. TREM2 activation can partially compensate for CSF1R loss of function, providing a rationale for therapeutic TREM2 agonism[^5]. |
| Dysfunctional phagocytosis | Microglial phagocytic capacity is impaired, leading to accumulation of cellular debris. |
| Pigmented glia | Characteristic pigmented macrophages accumulate in affected white matter. |
| White matter degeneration | Progressive demyelination with relative preservation of subcortical U-fibers. Loss of axons and myelin proceeds in a frontoparietal-to-occipital gradient. |
| Corpus callosum thinning | Atrophy of the corpus callosum, particularly the body and splenium, is a characteristic feature. |
| Executive dysfunction | Impaired planning, judgment, and abstract thinking — often the earliest and most prominent cognitive deficit. |
| Behavioral changes | Apathy, disinhibition, personality changes, and social conduct problems. |
| Databases | OMIMOrphanetClinicalTrialsPubMed |
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