White matter disorders at the intersection of transcription, RNA processing and translation

Hereditary white matter disorders, encompassing leukodystrophies and genetically determined leukoencephalopathies, are a heterogeneous group of conditions characterized by white matter signal abnormalities on neuroimaging. An increasing number of these disorders are now associated with defects in genes that encode proteins involved in transcription, RNA processing and translation. Pathogenic variants in these genes disrupt fundamental processes of the central dogma yet manifest primarily as neurological diseases, often presenting with diverse clinical and radiological features. Although many of these conditions have been recognized for over a decade, their underlying pathophysiological mechanisms and the selective vulnerability of the CNS and myelin remain incompletely understood. Here we provide a comprehensive overview of white matter disorders arising from defects in protein biosynthesis pathways. We summarize known disease-causing genes and their molecular consequences and associated clinical and radiological phenotypes, and highlight emerging mechanistic themes and therapeutic strategies across this expanding class of disorders.