Chapter 1 18 disorders, the leuko-axonopathies, are due to defects in neuron- or axon-specific gene products or they have central disease mechanisms which can be conducted back to axons (van der Knaap & Bugiani, 2017). For example, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is caused by variants in the TUBB4A gene, a gene coding for microtubules highly expressed in the brain (Hamilton et al., 2014). For others such as 4H leukodystrophy the affected gene is generic, but histopathology shows widespread axonal damage, pointing towards important neuroaxonal involvement. However, many end stage brain disorders involve neuronal damage without providing insight in the initial problems (Wolf, 2014). Astrocytes While neurons and oligodendrocytes have obvious roles in myelination, other brain cell types, such as astrocytes, also play crucial roles. Astrocytes perform various essential functions, including maintaining brain homeostasis, supporting the blood-brain barrier, and regulating neurotransmitter and lipid metabolism (Hasel et al., 2023). They are morphologically and functionally diverse, exhibiting regional differences in identity and specialization. Some genetic white matter disorders are known to be caused by variants in astrocyte-specific genes or in which astrocytes play crucial roles in the disease mechanisms and are referred to astrocytopathies (van der Knaap & Bugiani, 2017). For example, Alexander disease is a rare genetic astrocytopathy caused by variants in GFAP, which codes for glial fibrillary acidic protein (GFAP), an astrocyte-specific cytoskeletal intermediate filament protein (Brenner et al., 2001). For vanishing white matter (VWM) the causative gene is not astrocyte-specific but astrocytes are still central in the pathomechanisms of vanishing white matter. In vitro cultures have shown that VWM astrocytes secreted factors affect the oligodendrocyte lineage (Dooves et al., 2016). Microglia Microglia may also have an indirect role in 4H-related hypomyelination. Unlike other brain cells, microglia are thought to originate from erythro-myeloid progenitors (EMPs) in the developing yolk sac, making them of mesodermal lineage. Microglia play a dual role in immune defence and brain homeostasis by regulating neurogenesis, promoting neuronal survival, and performing synaptic pruning, thereby enhancing neural network efficiency and maturation (Paolicelli & Ferretti, 2017). Emerging research has begun to explore microglial in 4H leukodystrophy (Moir et al., 2024). Microgliopathies are observed in some white matter disorders, specifically CSF1R-related disorders, of which the gene is mainly expressed in
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