EIF2B5 was first associated with autosomal recessive leukoencephalopathy with vanishing white matter in 2001 (Leegwater et al., PMID: 11704758). 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) and Cree leukoencephalopathy. 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 5 (OMIM:603945, MONDO:0957873).
Twelve variants (missense, nonsense) that have been reported in 8 probands in 5 publications (PMIDs: 19158808, 15136673, 21484434 30014503, 17646634) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence, (PMIDs: 33300869, 20826436). The mouse model of EIF2B5 related leukoencephalopathy exhibits motor deficits, myelin degeneration, abnormal density of oligodendrocytes and astrocytes, and increased sensitivity to brain insult, which recapitulates the human disease. The zebrafish model is associated with impaired motor behavior and myelin defects. In summary, definitive evidence supports the relationship between EIF2B5 and leukoencephalopathy with vanishing white matter 5. 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 July 22, 2024 (SOP Version 10).
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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