EIF2B3 – Vanishing White Matter Disease

Leukoencephalopathy with vanishing white matter (VWM; MONDO:0800448) is an autosomal recessive leukodystrophy characterized by stress-provoked episodes of rapid neurological decline and chronic white matter rarefaction (PMID:15670229). EIF2B3 (HGNC:3259) encodes the γ-subunit of the eukaryotic translation initiation factor eIF2B, and pathogenic biallelic variants disrupt guanine nucleotide exchange factor (GEF) activity, leading to impaired protein synthesis under stress and progressive demyelination (PMID:11835386).

Initial case reports identified compound heterozygous missense variants in adult-onset VWM, including c.260C>T (p.Ala87Val) and c.272G>A (p.Arg91His) in a 29-year-old woman presenting with confusion, headaches, and ovarian failure (PMID:22312164). Subsequent adult cases confirmed c.260C>T (p.Ala87Val) in differential diagnosis of primary progressive multiple sclerosis (PMID:25135182). Prenatal onset with homozygous c.97A>G (p.Lys33Glu) in two siblings highlighted early manifestations and segregation in consanguineous families (PMID:28597716).

A multi-center study of 341 patients across 87 reports identified over 180 distinct EIF2B3 mutations, predominantly missense (86%) with occasional nonsense and frameshift changes, reinforcing autosomal recessive inheritance and extensive allelic heterogeneity (PMID:34745209). Founder effects such as the c.260C>T (p.Ala87Val) allele in Quebec were noted in French-Canadian patients, with recurrent homozygosity in three unrelated individuals (PMID:25079571).

Functional assays demonstrate variable effects on eIF2B complex integrity and GEF activity: several patient-derived and recombinant complexes show reduced activity under stress, correlating imperfectly with clinical severity (PMID:21560189, PMID:26285592). An eif2b3-null zebrafish model recapitulates myelin defects, glial dysregulation, and ectopic angiogenesis, validating novel alleles including c.503T>C (p.Leu168Pro) (PMID:33517449). iPSC-derived cerebral organoids from EIF2B3 mutants exhibit unfolded protein response activation, delayed neuronal differentiation, and oligodendrocyte paucity (PMID:36650674).

No studies to date have refuted the EIF2B3–VWM link; rather, disparate models and broad phenotypic spectra from antenatal to adult onset converge on a loss-of-function mechanism. The robust genetic and functional data fulfill ClinGen criteria for a Definitive gene-disease relationship.

Key Take-home: Genetic testing of EIF2B3 is critical for early diagnosis of VWM across age ranges; variant identification guides prognosis, family planning, and supports emerging therapeutic trials targeting eIF2B downstream pathways.

References

• Journal of paediatrics and child health • 2005 • Vanishing white matter disease in a child presenting with ataxia. PMID:15670229
• Annals of neurology • 2002 • Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. PMID:11835386
• Archives of neurology • 2012 • Adult-onset vanishing white matter disease due to a novel EIF2B3 mutation. PMID:22312164
• Multiple sclerosis • 2015 • Adult-onset vanishing white matter disease as differential diagnosis of primary progressive multiple sclerosis: a case report. PMID:25135182
• Journal of child neurology • 2017 • Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings. PMID:28597716
• Frontiers in genetics • 2021 • Correlation Between Genotype and Age of Onset in Leukoencephalopathy With Vanishing White Matter. PMID:34745209
• Pediatric neurology • 2014 • Vanishing white matter disease in French-Canadian patients from Quebec. PMID:25079571
• Human mutation • 2011 • Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes. PMID:21560189
• BMC medical genetics • 2015 • Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (eIF) 2B associated with Vanishing White Matter disease. PMID:26285592
• Human molecular genetics • 2021 • Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish. PMID:33517449
• CNS neuroscience & therapeutics • 2023 • Human-induced pluripotent stem cell-derived cerebral organoid of leukoencephalopathy with vanishing white matter. PMID:36650674

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