Correlation Between Genotype and Age of Onset in Leukoencephalopathy With Vanishing White Matter

Abstract

Purpose: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy caused by mutations in any of the five genes encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). The severity of the disease varies considerably, and its genotypic-phenotypic correlation is still unclear. Age of onset is the only independent clinical predictor for VWM severity. In this study, the correlation between genotype and age at onset of patients was investigated.Methods: Data were collected from patients with VWM in the available literature reports and from those diagnosed in Peking University First Hospital. The age of onset was divided into early-onset (≤4 years) and late-onset type (>4 years) for the analysis of the correlation between genotype and age of onset in patients with VWM.Results: A total of 341 patients were included, 281 were reported in 87 available articles and 60 were diagnosed in our center. A total of 180 different mutations were found, among which 86.1% were missense. The gene (EIF2B1-5) in which the mutation located, and the number of null alleles were not associated with age of onset in these patients. Certain mutations such as eIF2Bε[Arg195His] and eIF2Bε[Arg269Gln] that were predicted to have a serious influence on eIF2B structure were related to earlier age of onset. EIF2Bγ[Ala87Val] which was predicted to have a minimal influence on eIF2B structure, was related to later age of onset. Whereas eIF2Bβ[Glu213Gly], eIF2Bβ[Gly200Val] and eIF2Bε[Thr91Ala], also predicted having a small effect on the structure of eIF2B, did not show correlation with the age of onset. The onset age of patients with one or biallelic missense mutations located in the catalytic domain or other homologous domains in catalytic subunits (eIF2Bγ, ε) was earlier than that of patients with biallelic mutations located in the NT domain.Conclusion: The onset age of patients with different genotypes varied greatly. The degree of influence in protein structure of some missense mutations was correlated with phenotypic severity, but the results were not completely consistent. The combined effect of biallelic mutations, the role of regulatory genes, environmental stress and other potential factors on phenotypes need to be further explored.

The Coexistence of Two Genetic Astrocytopathies—Megalencephalic Leukoencephalopathy and Vanishing White Matter Disease—in an Indian Child

“…6 Missense mutations of EIF2B1-5 showed variable effects on the structure of the protein and the ages of symptom onset with eIF2B [Arg195His] and eIF2B [Arg269Gln] mutations linked to an earlier age of onset, eIF2Bγ [Ala87Val] variation linked to a later age of onset, and eIF2Bβ [Glu213Gly], eIF2Bβ [Gly200Val], and eIF2B [Thr91Ala] mutations not linked to the age of onset. 7,8 The missense variant of EIF2B3:c.674G > A (p.Arg225Gln) in the index case caused substitution of arginine to glutamine at 225, and the variant had been reported by ClinVar as pathogenic. [9][10][11] There is a small physicochemical difference between arginine and glutamine.…”

Human‐induced pluripotent stem cell‐derived cerebral organoid of leukoencephalopathy with vanishing white matter

“…1,2 We diagnosed the first child with VWM in China in 2007 3 and have so far diagnosed 60 Chinese children with VWM. 4 Neuropathology from autopsy samples showed sparseness of deep white matter, increased cystic degeneration without reactive astrocytes proliferation, dysmorphic immature astrocytes, increased oligodendrocytes precursor cells, and foamy oligodendrocytes. 5 In particular, neuropathological findings from two fetuses with EIF2B5 gene mutations presented in utero growth retardation and microcephaly with simplified gyral pattern, which indicated the disease might occur from early gestation and may apparent from the second half of pregnancy by a severe impairment of brain development.…”

“…The typical manifestation is progressive motor regression, accompanied by ataxia and epileptic seizures in some patients, and exacerbated by fever or head trauma 1,2 . We diagnosed the first child with VWM in China in 2007 3 and have so far diagnosed 60 Chinese children with VWM 4 . Neuropathology from autopsy samples showed sparseness of deep white matter, increased cystic degeneration without reactive astrocytes proliferation, dysmorphic immature astrocytes, increased oligodendrocytes precursor cells, and foamy oligodendrocytes 5 .…”