Genetic Mechanisms of Adult-Onset Leukoencephalopathy

Adult-onset leukoencephalopathy encompasses a group of genetically driven disorders characterised by progressive degeneration of cerebral white matter. Mutations in genes such as CSF1R and AARS2 disrupt critical cellular processes in microglia and oligodendrocyte lineages, leading to demyelination, axonal spheroids and neuroinflammation. Loss-of-function and haploinsufficiency in tyrosine kinase receptors, as well as intronic mis-splicing events, compromise receptor signalling and myelin maintenance. Recent mechanistic studies have revealed that aberrant microglial activation, failure of oligodendrocyte precursor cell maturation and impaired autophagy converge to drive white matter loss. The global burden of these disorders has prompted advances in genetic diagnostics, with long-read sequencing improving the detection of structural variants and splicing defects. An improved understanding of molecular underpinnings offers avenues for targeted therapies, including modulation of microglial function and gene-directed interventions.

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Genetic Mechanisms of Adult-Onset Leukoencephalopathy publication trend

The graph below shows the total number of articles in genetic mechanisms of adult-onset leukoencephalopathy across all publications each year (not limited to Nature Index journals).

Technical terms

Leukoencephalopathy: A disorder primarily affecting the brain’s white matter, often leading to cognitive and motor deficits.

CSF1R: Colony-stimulating factor-1 receptor, a tyrosine kinase essential for microglial survival and function.

Microglia: Resident immune cells of the central nervous system that participate in debris clearance and inflammatory responses.

Oligodendrocyte precursor cell (OPC): A progenitor cell that differentiates into oligodendrocytes, the myelin-forming cells of the brain.

Exon skipping: A splicing error in which an exon is omitted from the mature mRNA, often resulting in a truncated protein.

Haploinsufficiency: A condition in which a single functional copy of a gene does not produce enough protein to maintain normal function.

References

1. Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study. Acta Neuropathologica Communications (2024).
2. Identification and characterization of a novel intronic splicing mutation in CSF1R‐related leukoencephalopathy. CNS Neuroscience & Therapeutics (2024).
3. Redefining the phenotype of ALSP and AARS2 mutation–related leukodystrophy. Neurology Genetics (2017).
4. Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy. Translational Neurodegeneration (2019).