Vanishing white matter disease: A review with focus on its genetics

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive brain disorder, most often with a childhood onset. Magnetic resonance imaging and spectroscopy indicate that, with time, increasing amounts of cerebral white matter vanish and are replaced by fluid. Autopsy confirms white matter rarefaction and cystic degeneration. The process of localization and identification of the first two genes related to VWM, EIF2B5 and EIF2B2, was facilitated by two founder effects in the Dutch population. EIF2B5 and EIF2B2 encode the ε and β subunits of translation initiation factor eIF2B. Soon it was shown that mutations in all five eIF2B subunit genes can cause VWM. EIF2B is essential for the initiation of translation of RNA into protein and is involved in regulation of the process, especially under stress conditions, which may explain the sensitivity to stress conditions observed in VWM patients. The pathophysiology of the disease is still poorly understood

Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease

Leukoencephalopathy with vanishing white matter (VWM) is a childhood white matter disorder with an autosomal-recessive mode of inheritance. The clinical course is chronic progressive with episodes of rapid neurologic deterioration after febrile infections. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B), a protein complex that is essential for protein synthesis. In VWM, mutations in the eIF2B genes are thought to impair the ability of cells to regulate protein synthesis under normal and stress conditions. It has been suggested that the pathophysiology of VWM involves inappropriate activation of the unfolded protein response (UPR). The UPR is a protective mechanism activated by an overload of unfolded or malfolded proteins in the endoplasmic reticulum. Activation of one pathway of the UPR, in which eIF2B is involved, has already been described in brain tissue of patients with VWM. In the present study, we demonstrate activation of all 3 UPR pathways in VWM brain tissue using real-time quantitative polymerase chain reaction and immunohistochemistry. We show that activation occurs exclusively in the white matter, predominantly in oligodendrocytes and astrocytes. The selective involvement of these cells suggests that inappropriate UPR activation may play a key role in the pathophysiology of VWM

The unfolded protein response in vanishing white matter disease

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocvtes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2α (eIF2αP) and combined immunohistochemical and Western blot analysis of the down-stream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM

D5.3 – Pilots quality report round 1

This deliverable presents the implementation details of the first round of pilots run by WP5 partners between May and October 2017, using games created by game developers with RAGE ecosystem's assets. The first-round pilots are aimed at collecting preliminary results for a first evaluation of the games, with the goal of feeding back useful information to development for the final versions of games and assets. The results presented in this document are complimentary with those reported in D8.3 where the analysis of scientific aspects is presented.This study is part of the RAGE project. The RAGE project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 644187. This publication reflects only the author's view. The European Commission is not responsible for any use that may be made of the information it contains