Abstract
Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the ɛ- and β-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.
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Acknowledgements
We thank the affected families, the United Leukodystrophy Foundation and the referring doctors for their participation. Tissue specimens were obtained from the National Neurological Research Specimen Bank, Veterans Administration Medical Center, Wadsworth Division, Los Angeles, which is sponsored by the National Institute of Neurological Disorders and Stroke/National Institute of Mental Health, the National Multiple Sclerosis Society, the Hereditary Disease Foundation and the Veterans Health Services and Research Administration, Department of Veterans Affairs. We thank B. Kuyt for genealogical research and A.A.M. Thomas and J.M. Powers for critical reading of the manuscript. This work was supported by the Dutch Organisation for Scientific Research (NWO, grant 903-42-097) and the Dr. W.M. Phelps Foundation for Spastics (grant 00026WO).
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Leegwater, P., Vermeulen, G., Könst, A. et al. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 29, 383–388 (2001). https://doi.org/10.1038/ng764
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DOI: https://doi.org/10.1038/ng764
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