EIF2B5 – Leukoencephalopathy with Vanishing White Matter

Leukoencephalopathy with vanishing white matter (VWMD) is an autosomal recessive leukodystrophy characterized by chronic and episodic neurological deterioration, often precipitated by fever or minor head trauma. The disease manifests with cerebellar ataxia, tremor, spasticity, and variable seizures, reflecting widespread white matter rarefaction and cystic degeneration on MRI. Bi‐allelic mutations in EIF2B5, encoding the ε‐subunit of eukaryotic initiation factor 2B, are a primary cause of VWMD (PMID:11704758).

Genetic studies have identified pathogenic EIF2B5 variants in at least 29 unrelated families involving 29 probands in the initial report, with subsequent screens adding >50 more patients across multi‐ethnic cohorts, totaling over 100 probands (PMID:11704758; PMID:15776425; PMID:19158808). Inheritance is autosomal recessive, with affected individuals typically compound heterozygous or homozygous for missense or loss‐of‐function alleles.

The variant spectrum encompasses missense substitutions, nonsense and frameshift mutations, splice‐site changes, and noncanonical intronic alterations. A recurrent allele, c.1264C>T (p.Arg422Ter), has been reported in multiple patients, while founder and population‐specific variants such as p.Arg113His are enriched in Dutch cohorts. Deep intronic and hypomorphic splice‐site variants (e.g., c.1156+13G>A) contribute to late‐onset or milder phenotypes.

Functional assays demonstrate that VWMD‐associated EIF2B5 mutations impair guanine nucleotide exchange activity of the eIF2B complex, reduce complex assembly, or perturb substrate binding in vitro (PMID:15060152). Patient‐derived glial cultures reveal compromised GFAP+ astrocyte generation with aberrant morphology (PMID:15723074). In vivo, Eif2b5I98M mutant mice exhibit reduced white matter development, ER stress activation, and glial pathology, modeling human VWMD neuropathology (PMID:31587290).

Clinically, EIF2B5‐related VWMD presents across a broad age spectrum—from antenatal hypomyelination and perinatal growth retardation to adult‐onset ovarioleukodystrophy with ovarian failure. Core neurologic features include ataxia (HP:0001251), tremor (HP:0001337), seizures (HP:0001250), and spasticity (HP:0001257). MRI hallmarks are diffuse cerebral white matter rarefaction, cystic change, and relative U‐fiber sparing.

References

• Nature Genetics • 2001 • Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter PMID:11704758
• Human Mutation • 2005 • Identification of ten novel mutations in patients with eIF2B-related disorders PMID:15776425
• Journal of Human Genetics • 2009 • Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease PMID:19158808
• 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
• Nature Medicine • 2005 • EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy PMID:15723074
• Journal of Neurochemistry • 2020 • Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model PMID:31587290

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