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Introduction and Methods Vanishing whitematter disease (VWM) is one of the hereditary leukoencephalopathies inchildhood. Mutations in EIF2B1-5,encoding subunits of eukaryotic translation initiation factor 2B (eIF2B), areidentified in > 90% of patients. In this study, an average 4 year-follow-upwas performed in 34 gene-confirmed Chinese VWM patients. And in vitro study wasperformed in patients’ fibroblasts as well as in human oligodendrocyte lines toinvestigate the role of unfolded protein response (UPR) and autophagy in thepathogenesis. Results 34 patientswere consisted of 21 early childhood, 10 infantile and 3 juvenile types. Allshowed progressively rapid motor regression. The median survival time was 8.83±1.51years. 71% showed episodic aggravation during febrile diseases. Seizures occurredin 50%. In the in vitro study, UPR was overactivated under baseline conditionsand persisted after ER stress in human oligodentrocyes with mutant EIF2B3,which led to increased apoptosis and decreased cell viability. Meanwhile, theautophagy level was decreased in oligodentrocyes lines but not in patients’fibroblasts. The cell viability decreased, and apoptosis increased, even moreafter autophagy inhibition or UPR enhancement in the mutant oligodentrocyes. Itis suggested that excessive UPR and depressed autophagy after ERS may playimportant roles in the pathogenesis, especially in episodic aggravations in thecase of stress. Conclusions This isthe largest long term follow-up study in VWM, which is helpful for betterunderstanding of the natural history of this rare disease. Study on UPR andautophagy may provide evidence for future therapeutic targets.

Vanishing white matter disease; follow-up; UPR; Autophagy