Leukoencephalopathy with vanishing white matter (VWM disease) is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. The disease belongs to a family of conditions called the Leukodystrophies.
Symptoms and signs Onset usually occurs in childhood, however some adult cases have been found. Generally, physicians look for the symptoms in children. Symptoms include cerebellar ataxia, spasticity, optic atrophy, epilepsy, loss of motor functions, irritability, vomiting, coma, and even fever has been tied to VWM. The neurological disorders and symptoms which occur with VWM are not specific to countries; they are the same all over the world. Neurological abnormalities may not always be present in those who experience onset as adults. Symptoms generally appear in young children or infants who were previously developing fairly normally.
Causes VWM is a leukodystrophy which has unique biochemical abnormalities. A unique characteristic of VWM is that only oligodendrocytes and astrocytes are negatively affected while other glial cells and neurons seem to be unaffected. This is the central question behind VWM. The real reasons behind this behavior are unknown since the cells are in the brain and have been rarely studied. However, there is a theory which is generally accepted by most experts in the field. The main characteristic of these cells is the fact that they synthesize a lot of proteins. 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.
eIF2B's 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. This mutation has also been documented in rodents, but they do not acquire VWM, while humans do. Another common mutation is G584A found in the eIF2B5 subunit. A correlation with stress has also been made, as eIF2B plays a central role in stress management – it is essential in down regulation protein synthesis in different stress conditions – and VWM patients are highly sensitive to stress. Protein eIF2B exists in all cells, and if this protein is reduced enough the cell will be negatively affected, and if it is reduced to zero, the cell will die. In affected cells, the protein is reduced to about 50%, which is acceptable for functionality in most cells, but not in glial cells since they synthesize a large amount of proteins constantly and need as many functioning proteins within them as possible. This would lower the baseline of the amount of stress a cell can handle, and thus in a stressed environment, it would have detrimental effects on these cells. Mutations in three of the subunits of eIF2B (2,4,&5) has been seen in both VWM and premature ovarian failure. The North American Cree population has also been found to have a distinctive mutation, R195H, which can lead to VWM. All patients who have been studied only have one mutation present in the gene, causing the eIF2B to still be active, which leads to VWM. If two mutations occurred, then eIF2B activity would be stopped by the body.
Neuropathology Upon autopsy, the full effect of VWM has been documented. The gray matter remains normal in all characteristics while the white matter changes texture, becoming soft and gelatinous. Rarefaction of the white matter is seen through light microscopy and the small number of axons and U-fibers that were affected can also be seen. Numerous small cavities in the white matter are also apparent. The key characteristic that sets VWM apart from the other leukodystrophies is the presence of foamy oligodendrocytes. These foamy oligodendrocytes tend to have increased cytoplasmic structures, a greater number of irregular mitochondria and a higher rate of apoptosis. Abnormally shaped astrocytes with fibrile infections are very prevalent throughout the capillaries in the brain. Strangely, astrocytes are affected more than oligodendrocytes; there is even a reduction in the astrocyte progenitors, yet axons remain relatively unharmed.
Diagnosis Most diagnosis occurs in the early years of life around 2 to 6 years old. There have been cases in which onset and diagnosis have occurred late into adulthood. Those with onset at this time have different signs, particularly the lack of cognitive deterioration. Overall, detection of adult forms of VWM is difficult as MRI was not a common tool when they were diagnosed. Common signs to look for include chronic progressive neurological deterioration with cerebellar ataxia, spasticity, mental decline, decline of vision, mild epilepsy, hand tremor, the ability to chew and swallow food becomes difficult, rapid deterioration and fibrile infections following head trauma or fright, loss of motor functions, irritability, behavioural changes, vomiting, and even coma. Those who go into coma, if they do come out usually die within a few years. The diagnosis can be difficult if the physician does not take an MRI.
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