Hypomyelinating leukodystrophy: From molecular mechanisms to clinical advances

Abstract

Hypomyelinating leukodystrophies (HLDs) are a group of inherited disorders characterized by impaired myelin formation in the central nervous system. Among them, Pelizaeus-Merzbacher disease (PMD) is a well-defined X-linked leukodystrophy caused by mutations in the PLP1 gene, including duplications, missense variants, and null mutations. Recent studies have revealed that different types of PLP1 mutations lead to distinct pathomechanisms: while missense mutations induce endoplasmic reticulum stress and activate the unfolded protein response (UPR), PLP1 duplications cause aberrant intracellular trafficking and cholesterol accumulation without UPR activation. Additionally, mutations in other genes such as GJC2, SOX10, TUBB4A, and POLR3A/B have been implicated in various forms of HLD, each with unique clinical and imaging features. Advances in neuroimaging and next-generation sequencing have enabled more accurate and earlier diagnosis, expanding the clinical spectrum and deepening our understanding of disease mechanisms. This review summarizes the current knowledge on the molecular pathogenesis, genotype–phenotype correlations, and diagnostic approaches in HLDs, with an emphasis on recent biological insights that may inform future therapeutic strategies.