Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter

TLDR

Leukoencephalopathy with vanishing white matter is an autosomal recessive, chronically progressive disorder that worsens with fever or minor head trauma, and is primarily caused by mutations in the ε or β subunits of the five‑subunit translation initiation factor eIF2B, which regulates protein synthesis under stress. The study performed mutation screening of the α, γ, and δ subunits of eIF2B and the α subunit of eIF2 to identify pathogenic variants. Pathogenic variants were found in the α, γ, and δ subunits of eIF2B in five patients, with no mutations in eIF2α, confirming that mutations in all five eIF2B subunits can cause VWM and explaining the disease’s sensitivity to stress.

Abstract

Abstract Leukoencephalopathy with vanishing white matter is a recently defined autosomal recessive disorder. The course is chronic progressive with additional episodes of rapid deterioration, provoked by fever and minor head trauma. A previous study showed that mutations in the genes encoding the ε‐ or the β‐subunit of the eukaryotic translation initiation factor eIF2B, a complex consisting of five subunits, cause the disease in most patients. Seven unsolved patients remained. The unsolved patients were investigated by mutation analysis of the genes encoding the α‐, γ‐, and δ‐subunit of eIF2B and the gene encoding the α‐subunit of eIF2, because phosphorylation of this latter subunit regulates eIF2B activity. Mutations were found in the genes encoding the α‐ (1 patient), γ‐ (2 patients), and δ‐subunits (2 patients) of eIF2B, but no mutations were found in the gene encoding the α‐subunit of eIF2. In 2, both less typical patients, no mutations were found. Mutations in all five genes eIF2B subunit genes can cause VWM. eIF2B is essential for the initiation of translation of RNA into protein and is involved in regulation of the process, especially under circumstances of stress, such as fever. A defect in eIF2B may explain the sensitivity to stress factors in vanishing white matter patients.