These cells produce a large amount of proteins from a small amount of precursors and so are constantly working and under a reasonable amount of stress. So with a mutation in eIF2B, slight increases in the amount of stress these cells encounter occur, making them more susceptible to failure due to stress. The large amount of oligodendrocytes which display apoptotic characteristics and express apoptotic proteins suggests cell number reduction in the early stages of the disease. Premature ovarian failure has also been associated with diminishing white matter. However through an intensive survey, it was determined that even if an individual has premature ovarian failure, she does not necessarily have VWM. eIF2Bs role
eIF2B is the guanine nucleotide-exchange factor for eIF2, and is composed of 5 subunits. The largest subunit, eIF2B5 contains the most mutations for VWM. eIF2B is a complex which is very involved with the regulation of in the translation of mRNA into proteins. eIF2B is essential for the exchange of guanosine diphosphate(GDP) for guanosine-5-triphosphate(GTP) in the initiation of translation via eIF2, because eIF2 is regenerated through this exchange. A decrease in eIF2B activity has been correlated with the onset of VWM. A common factor among VWM patients is mutations in the five subunits of eIF2B (21 discovered thus far), expressed in over 60% of the patients. These mutations lead to the decreased activity of eIF2B. The most common mutation is R113H, which is the mutation of histidine to arginine. The homozygous form of the mutation is the least severe form.
In VWM, the cells never produce the normal amounts, whereas with diseases like MS, the cells normal amounts are deteriorated. Also, with MS, the demyelination occurs due to inflammation, which is not the case in VWM. Cell differences include a lower penetration of the macrophages and microglia, as well as the lack of T cells and B cells in VWM. Finally, patients with MS have widespread demyelination, but those with VWM only express demyelination in a localized area.Some atypical forms of multiple sclerosis (multiple sclerosis with cavitary lesions) can be specially difficult to differentiate but there are some clues in MRI imaging that can help. Treatment
There are no treatments, only precautions which can be taken, mainly to reduce trauma to the head and avoiding physiological stress. Melatonin has been shown to provide cytoprotective traits to glial cells exposed to stressors such as excitotoxicity and oxidative stress. These stressors would be detrimental to cells with a genetically reduced activity of protein eIF2B. However, research connecting these ideas have not been conducted yet. Epidemiology
Extensive pathological and biochemical tests were performed, however the cause was found by studying a small population in which mutations in the eIF2B gene were found. No effective systemic studies have been conducted to determine the incidence around the world, but through the studies conducted thus far, it appears to be more prevalent in the white populations. VWM appears to have a lower number of cases in the Middle East, and Turkey has not yet had a reported case.