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English: FIGURE 1. Diverse mechanisms and cell types contribute to hypomyelination in leukodystrophies. In oligodendrocytes, mutations in myelin structural proteins (CNP, PLP1) can lead to thinner myelin sheaths and paranodal loop malformation (CNTNAP1, MAG, MAL). PLP mutations can also lead to aberrant protein aggregation. Other mutations can affect the function of organelles that participate in lipid metabolism and catabolism, such as peroxisomes (ABCD1, HSD17B4, PEX family genes) and lysosomes (ARSA, FUCA1, GALC, GLA, GLB1, PSAP). These defects can also lead to toxic lipid accumulation that builds up in the bloodstream (GLA) or activate astrocytes and microglia (ARSA). Finally, mutations affecting transcription factors (NKX6-2, SOX10), transcriptional machinery (POLR3 genes) and translation machinery (DARS1, eIF2B genes, EPRS1, RARS1) cause impair differentiation of oligodendrocytes and reduce production of myelin proteins. Defects in microtubules that project toward and within the myelin sheath (TUBB4A) as well as in PI4K signaling pathways that contribute to wrapping (FAM126A) can affect myelin sheath growth. Mutations in mitochondrial genes can lead to lipid processing defects (CYP27A1), aberrant activation of apoptotic pathways (AIFM1), and metabolic issues (D2HGDH, IHD2, L2HGDH, SLC25A1). Other pathways, such as nuclear envelope integrity (LB1) and zinc efflux (TMEM163) can also affect oligodendrocyte health. In astrocytes, intermediate filament protein mutations (GFAP) can lead to its aggregation and formation of Rosenthal fibers. Mutations affecting gap junctions can disrupt cell junctions between astrocytes and oligodendrocytes (GJA1, GJC2) and between astrocytes and vasculature (HEPACAM/GLIALCAM, MLC1). Mutations affecting nucleic-acid sensors (ADAR1, IFIH1, RNASEH2 genes, SAMHD1, TREX1) can activate an immune response and release of interferons from astrocytes. In microglia, mutations in cytokine receptors (CSF1R) can affect microglial proliferation, differentiation, and activation. Finally, mutations affecting lipid processing (ARSA, D2HGDH, IHD2, L2HGDH, SLC25A1) can lead to aberrant lipid accumulation, which can activate microglia and astrocytes.