Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter

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, e ncoding the epsilon- and beta -subunits of the translation initiation facto r eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 fami lies. We also found two distantly related individuals who were homozygous w ith respect to a missense mutation in EIF2B2, affecting a conserved amino a cid. Three other patients also had mutations in EIF2B2. As eIF2B has an ess ential role in the regulation of translation under different conditions, in cluding stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously be en implicated in disease.