EIF2B2 – Vanishing White Matter Disease

Vanishing white matter disease (VWMD) is an autosomal recessive leukoencephalopathy characterized by chronic and episodic neurological deterioration often precipitated by fever or minor head trauma. Biallelic variants in EIF2B2 disrupt the beta-subunit of the eukaryotic translation initiation factor eIF2B complex, impairing global and mRNA-specific translation regulation and leading to white matter rarefaction and cystic degeneration (PMID:11704758).

Autosomal recessive inheritance has been confirmed in over 25 unrelated probands from more than 10 families, with segregation of biallelic EIF2B2 variants and no heterozygous carriers showing disease signs (PMID:11704758; PMID:25031760). Clinical presentations include childhood-onset ataxia and tremor, variable early-onset forms with hypotonia, cataracts, hepatomegaly, and episodic metabolic disturbances (PMID:22729508; PMID:22992991).

The spectrum of EIF2B2 variants includes missense, nonsense, frameshift, and splice-site mutations. The c.638A>G (p.Glu213Gly) variant has been reported in multiple cohorts associated with slow-progressive phenotypes (PMID:22729508). Recurrent alleles appear population-specific, such as p.Val85Glu in Saudi patients (PMID:25031760).

Functional studies demonstrate that frameshift and nonsense EIF2B2 mutations lead to null alleles failing to assemble into the eIF2B holocomplex, while missense mutations impair substrate binding and guanine nucleotide exchange factor (GEF) activity (PMID:15060152). iPSC-derived cerebral organoids with EIF2B2 mutations show delayed neuronal development, astrocyte immaturity, oligodendrocyte deficiency, UPR overactivation, and sparse myelination, mirroring human pathology (PMID:36650674).

No studies refute the association between EIF2B2 loss-of-function variants and VWMD. Divergent phenotypic expressivity appears more related to mutation-specific effects on eIF2B function than to alternative mechanisms.

Overall, robust genetic evidence, segregation data, and concordant functional findings support a Strong gene–disease association for EIF2B2 in vanishing white matter disease. Early molecular diagnosis of EIF2B2 variants informs prognosis, management of stress-triggered episodes, and genetic counseling.

References

• Nature Genetics • 2001 • Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. PMID:11704758
• International Journal of Clinical and Experimental Pathology • 2014 • An autopsy case of infantile-onset vanishing white matter disease related to an EIF2B2 mutation (V85E) in a hemizygous region. PMID:25031760
• Neurological Sciences • 2013 • Vanishing white matter disease: an Italian case with A638G mutation in exon 5 of EIF2B2 gene, an unusual early onset and a long course. PMID:22729508
• Molecular and Cellular Biology • 2004 • Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. PMID:15060152
• CNS Neuroscience & Therapeutics • 2023 • Human-induced pluripotent stem cell-derived cerebral organoid of leukoencephalopathy with vanishing white matter. PMID:36650674

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