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Leukoencephalopathy with vanishing white matter: a review
Marianna Bugiani1, Ilja Boor, James M Powers
1Departments of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands.
Journal of Neuropathology and Experimental Neurology
|September 15, 2010
Summary
Vanishing white matter (VWM) is a rare leukoencephalopathy caused by mutations in the eukaryotic translation initiation factor 2B (eIF2B) genes. These mutations impair protein synthesis regulation, leading to cellular stress and neurological decline.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Vanishing white matter (VWM) is a prevalent inherited leukoencephalopathy affecting all ages.
- Characterized by progressive cerebellar ataxia, VWM involves neurological deterioration triggered by minor stressors.
- Pathological hallmarks include white matter rarefaction, cystic degeneration, and characteristic foamy oligodendrocytes.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Vanishing White Matter (VWM).
- To understand the role of eukaryotic translation initiation factor 2B (eIF2B) in VWM pathogenesis.
- To investigate the selective vulnerability of glial cells in VWM.
Main Methods:
- Genetic analysis of mutations in eIF2B genes (EIF2B1-EIF2B5).
- Assessment of eIF2B complex activity and protein synthesis regulation.
- Investigation of the unfolded protein response (UPR) pathway activation.
Main Results:
- Mutations in eIF2B genes reduce eIF2B activity, impairing protein synthesis control.
- Reduced eIF2B function leads to sustained improper activation of the unfolded protein response.
- VWM cells exhibit constitutive predisposition and hyperreactivity to cellular stress.
Conclusions:
- VWM pathogenesis involves dysregulated protein synthesis and aberrant UPR activation due to eIF2B mutations.
- The precise mechanisms driving selective glial vulnerability in VWM require further investigation.
- Understanding these pathways may offer therapeutic targets for VWM and related disorders.
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