EIF2B1 related leukoencephalopathy, autosomal recessive
The EIF2B1 gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis (NCBI Gene ID: 1967). EIF2B1 was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2002 (van der Knaap et al., PMID: 11835386). Affected individuals present with gait dysfunction, spasticity, cognitive decline, and white matter abnormalities on MRI. Some individuals develop ovarian failure. Onset is variable from infancy to adulthood, and progression of disease is often in the setting of fever, trauma, or stress. Vanishing white matter disease has also been referred to as Childhood Ataxia with Central Nervous System Hypomyelination (CACH). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that a phenotypic spectrum exists and there is no difference in molecular mechanism or inheritance pattern. Therefore, we chose to curate this gene-disease relationship under the disease term leukoencephalopathy with vanishing white matter 1 (OMIM:606686, MONDO:0020507).
Eight variants (missense, nonsense, canonical, small in-frame deletion) that have been reported in 9 probands in 8 publications (PMIDs: 11835386, 34302356, 18263758, 15776425, 32865661, 36801247, 25843247, 25761052) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence. Protein interaction studies have shown that the subunit encoded by EIF2B1 interacts with the four other EIF2B complex subunits that are encoded by genes (EIF2B2, EIF2B3, EIF2B4, and EIF2B5) definitively known to cause leukoencephalopathy with vanishing (PMID: 24532666). In summary, definitive evidence supports the relationship between EIF2B1 and autosomal recessive leukoencephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date February 5, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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