The brain of humans consists of gray matter and white matter. The gray matter contains nerve cells. The white matter of the brain is composed of nerve fibers, myelin, oligodendrocytes, which produces myelin, and astrocytes, which maintain homeostasis and produce gliosis in the case of damage. The nerve fibers form the connections between the nerve cells. Myelin is a fatty sheath wrapped around nerve fibers. The myelin sheath has two functions: insulation and acceleration of impulse conduction. Insulation is important for the prevention of short-circuits. Through its special construction, myelin accelerates the propagation of impulses along nerve fibers.
White matter disorders
In many neurological disorders in childhood, the white matter of the brain is predominantly involved. These are called “the white matter disorders”. The diagnosis is usually made on the basis of MRI findings. White matter abnormalities on MRI can have different bases on tissue level. It may be that there is a lack of myelin because the myelin was never made in sufficient amounts. It may be that the myelin was formed all right, but is now broken down and lost. It may be that innumerable vacuoles are formed within the myelin sheath. It may be that scar tissue is formed within the white matter. There may be increased amounts of water between the myelinated fibers, etc. Nerve fibers may be lost as well.
It is clear that the term “white matter disorders” comprises many different disorders which all have different consequences for brain function. The handicap for the child with a white matter disorder is highly variable, depending on what is happening at brain tissue level.
Vanishing White Matter
Vanishing White Matter (VWM) is one of the more common leukodystrophies (OMIM number 603896). The disease is clinically characterized by chronic progressive motor dysfunction, mainly cerebellar ataxia. Cognitive decline is less prominent in children, but in adults, it is more prominent than motor decline. Incidental epileptic seizures are observed. Patients usually experience chronic progressive neurological deterioration with episodes of rapid worsening that are triggered by stressors such as fever, infections, minor head trauma, and acute fright 1. The disease is fatal.
Initially, VWM was described as a childhood leukoencephalopathy, as the disease onset is most often in the early infantile period. Generally, early onset is associated with a more severe handicap, and patients with onset under the age of 4 years have a faster disease progression. However, it is becoming increasingly clear that VWM has a clinically wide spectrum, and also adult-onset patients with a milder disease course are diagnosed 2.
On magnetic resonance imaging (MRI), VWM displays a characteristic disease pattern; the cerebral white matter shows diffuse abnormalities with rarefaction and progressive cystic degeneration and is eventually replaced by fluid. The U-fibers, the outer blade of the corpus callosum, the internal capsules, and anterior commissure are relatively spared, for which no explanation is currently available. Also, the cerebellum is affected and is often atrophic in later stages. The cortical grey matter remains largely unaffected 1,3.
VWM brain pathology is characterized by white matter abnormalities, where the remaining myelin sheaths are thin and vacuolated. Also, axonal loss is observed in affected areas. The primary cell defect lies with the glial cells. The oligodendrocytes and astrocytes in the white matter are dysmorphic and show increased proliferation in combination with reduced maturation 4. There is an increased density of oligodendrocyte precursor cells (OPCs), which may have foamy cytoplasm, and a decreased number of mature oligodendrocytes, explaining the lack of myelin. There is meagre astrogliosis in the damaged white matter areas despite the severity of the damage, suggesting an astrocytic defect 1,4,5. In the affected CNS, the white matter astrocytes are dysmorphic and have blunt processes, and express immaturity marker Nestin 4. The Bergmann glia are displaced to the molecular layer in VWM mice and human VWM patients 6.
The clinical and MRI-based diagnosis is confirmed by genetic testing. VWM is caused by mutations in the genes coding for the subunits of eukaryotic translation initiation factor 2B (eIF2B) 7-9. This protein complex is essential in the regulation of the first steps of RNA translation and protein synthesis 9, and regulates thereby the rate of protein translation. Furthermore, eIF2B is an essential component of the integrated stress response (ISR). This is a molecular pathway that upregulates specific genes in response to internal or environmental stressors. In VWM the deregulation of ISR is central to the molecular mechanisms of the disease.
The eIF2B protein complex consists of 5 subunits, α–ε, which are encoded by the genes EIF2B1–5. The subunits have different functions: the eIF2Bγ and eIF2Bε subunits together form a catalytic complex, and the largest subunit eIF2Bε contains the catalytic domain that regulates the GDP/GTP exchange on eIF2. The eIF2Bα, eIF2Bβ, and eIF2Bδ subunits form the regulatory complex, and eIF2 directly phosphorylates the α-subunit, which results in the inactivation of the complex.
Mutations in any of the EIF2B1-5 genes causes VWM 9, and specific mutations in EIF2B5 and EIF2B2 have been identified as the founder mutations in the Dutch VWM population 10. The mutations are most frequent in EIF2B5 (57% of all mutations), followed by EIF2B4 (17%), EIF2B2 (15%), EIF2B3 (7%) and EIF2B1 (4%) 12. A genotype-phenotype correlation study demonstrated that the combination of mutations influences the clinical phenotype 13.
Initially, it was described that all mutations result in partial loss of eIF2B activity 14. Different mutations affected binding properties and activity in different ways, and even enhanced binding or enhanced translation of certain mRNAs was observed 15. A follow-up study showed that mutations not always affect the GEF activity or complex formation functions of eIF2B and that eIF2B activity does not correlate with disease severity 16. As eIF2B is a ubiquitously present protein complex in all cells, it is surprising that the CNS white matter shows selective vulnerability. Recent findings suggest that the eIF2B mutations result in deregulation of the ER function in VWM astrocytes 17.
Altogether, next to most leukodystrophies, VWM is a devastating disease for which currently no treatment is available. More literature about VWM research, including the most recent publications focusing on therapy development, can be found on our publication page.
- Bugiani, M., Boor, I., Powers, J. M., Scheper, G. C. & van der Knaap, M. S. Leukoencephalopathy with vanishing white matter: a review. J Neuropathol Exp Neurol 69, 987-996, doi:10.1097/NEN.0b013e3181f2eafa (2010).
- Hamilton, E. M. C. et al. The natural history of Vanishing White Matter. Ann Neurol, doi:10.1002/ana.25287 (2018).
- van der Knaap, M. S., Pronk, J. C. & Scheper, G. C. Vanishing white matter disease. Lancet Neurol 5, 413-423, doi:10.1016/S1474-4422(06)70440-9 (2006).
- Bugiani, M. et al. Defective glial maturation in vanishing white matter disease. J Neuropathol Exp Neurol 70, 69-82, doi:10.1097/NEN.0b013e318203ae74 (2011).
- Bugiani, M., Vuong, C., Breur, M. & van der Knaap, M. S. Vanishing white matter: a leukodystrophy due to astrocytic dysfunction. Brain Pathol 28, 408-421, doi:10.1111/bpa.12606 (2018).
- Dooves, S. et al. Astrocytes are central in the pathomechanisms of vanishing white matter. J Clin Invest 126, 1512-1524, doi:10.1172/JCI83908 (2016).
- Leegwater, P. A. et al. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 29, 383-388, doi:10.1038/ng764 (2001).
- Leegwater, P. A., Pronk, J. C. & van der Knaap, M. S. Leukoencephalopathy with vanishing white matter: from magnetic resonance imaging pattern to five genes. J Child Neurol 18, 639-645, doi:10.1177/08830738030180091101 (2003).
- van der Knaap, M. S. et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 51, 264-270 (2002).
- Pronk, J. C., van Kollenburg, B., Scheper, G. C. & van der Knaap, M. S. Vanishing white matter disease: a review with focus on its genetics. Ment Retard Dev Disabil Res Rev 12, 123-128, doi:10.1002/mrdd.20104 (2006).
- Wortham, N. C. & Proud, C. G. eIF2B: recent structural and functional insights into a key regulator of translation. Biochem Soc Trans 43, 1234-1240, doi:10.1042/BST20150164 (2015).
- Scali, O., Di Perri, C. & Federico, A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurol Sci 27, 271-277, doi:10.1007/s10072-006-0683-y (2006).
- van der Lei, H. D. et al. Genotype-phenotype correlation in vanishing white matter disease. Neurology 75, 1555-1559, doi:10.1212/WNL.0b013e3181f962ae (2010).
- Fogli, A. et al. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet 12, 561-566, doi:10.1038/sj.ejhg.5201189 (2004).
- Li, W., Wang, X., Van Der Knaap, M. S. & Proud, C. G. Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Mol Cell Biol 24, 3295-3306 (2004).
- Liu, R. et al. Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes. Hum Mutat 32, 1036-1045, doi:10.1002/humu.21535 (2011).
- Wisse, L. E. et al. Proteomic and Metabolomic Analyses of Vanishing White Matter Mouse Astrocytes Reveal Deregulation of ER Functions. Front Cell Neurosci 11, 411, doi:10.3389/fncel.2017.00411 (2017).