EIF2B5 – Leukoencephalopathy with Vanishing White Matter 5

Vanishing white matter disease type 5 (VWM5) is an autosomal recessive leukodystrophy caused by biallelic mutations in EIF2B5, encoding the ε‐subunit of eukaryotic initiation factor 2B (Gene Symbol; Disease Name). Patients present with early‐infantile to antenatal onset of progressive neurological decline characterized by cerebellar ataxia, spasticity, optic atrophy and seizures. MRI demonstrates diffuse white matter rarefaction and cystic degeneration.

Genetic evidence for EIF2B5 in VWM5 includes seven unrelated probands from four families with compound‐heterozygous or homozygous EIF2B5 variants and co‐segregation in affected sibships (e.g., c.1223T>C (p.Ile408Thr) in a Japanese infant) (PMID:25457085, PMID:32293553, PMID:33245593, PMID:37674283). The recurrent p.Arg195His (c.584G>A) allele, originally described in Cree leukoencephalopathy, underscores a founder effect in some populations.

The variant spectrum in EIF2B5 includes missense substitutions clustering in the catalytic and I-patch regions, loss-of-function frameshifts, splice-site mutations and hypomorphic intronic alleles (c.1156+13G>A) associated with milder adult‐onset ovarioleukodystrophy ([PMID:33245593]). Most pathogenic alleles are missense (≈80%), with residual guanine nucleotide exchange factor (GEF) activity correlating inversely with clinical severity.

Functional studies demonstrate that VWM5‐linked EIF2B5 mutations impair eIF2B complex formation, reduce GEF activity and dysregulate the integrated stress response. In vitro assays show heightened ER stress and constitutive ATF4 activation in cells expressing p.Arg195His ([PMID:19023445]) and partial loss of exchange activity for numerous point mutations ([PMID:15060152]).

Animal and cellular models recapitulate human pathology: Eif2b5I98M mice exhibit delayed myelination, astrocyte gliosis and failure to recover from demyelinating injury ([PMID:31587290]), while the Eif2b5R132H knock-in mouse shows hypomyelination and abnormal astroglial development ([PMID:20826436]). Cerebral organoids harboring EIF2B5 variants demonstrate impaired neuronal and oligodendrocyte maturation with overactivation of the unfolded protein response ([PMID:36650674]).

Collectively, the concordant segregation of biallelic EIF2B5 variants in multiple families and the reproducible functional impairment in cellular and animal models support a Strong gene–disease association. EIF2B5 deficiency leads to haploinsufficiency of eIF2B GEF function and maladaptive ER stress responses. Key Take-home: EIF2B5 genetic testing should be prioritized in infants and fetuses with rapidly progressive leukoencephalopathy, enabling accurate diagnosis, genetic counseling and eligibility for emerging therapies.

References

• Brain & development • 2015 • A Japanese girl with an early-infantile onset vanishing white matter disease resembling Cree leukoencephalopathy. PMID:25457085
• 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
• PloS one • 2008 • A point mutation in translation initiation factor 2B leads to a continuous hyper stress state in oligodendroglial-derived cells. PMID:19023445
• Acta neuropathologica communications • 2020 • Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination. PMID:32293553
• Annals of clinical and translational neurology • 2020 • A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy. PMID:33245593
• Journal of neurochemistry • 2020 • Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. PMID:31587290
• Brain : a journal of neurology • 2010 • A mouse model for eukaryotic translation initiation factor 2B-leucodystrophy reveals abnormal development of brain white matter. PMID:20826436
• Journal of genetics • 2023 • A novel missense variant in EIF2B5 identified in a consanguineous Iranian family with vanishing white matter disease and a brief review of the literature. PMID:37674283

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