Abstract
Vanishing white matter disease (VWM) is a rare autosomal recessive leukodystrophy caused by a mutation in any of the five gene encoding subunits of the translation initiation factors eIF2B1 to eIF2B5. Whole-exome sequencing was performed on a 7-year-old boy with prenatal symptoms, including intrauterine-growth retardation, decreased movements, and oligohydramnios as well as mild intellectual disability, optic atrophy, macrocephaly, mild ataxia, and white matter lesions after birth. Analysis of WES data revealed a homozygous missense variant, c.C590T (p.Thr197Met) in the EIF2B3 gene (NM_0203650). The candidate variant was confirmed by Sanger sequencing and found to co-segregate with disease in family members. Pathogenicity analysis, 3D protein modeling, and stability assessment showed the deleterious effects of this nucleotide change. Previous studies suggest a direct relationship between the onset of symptoms and the progression rate and severity of the disease. All described cases of EIF2B deficiency with antenatal-onset led prenatal death; if they were born, they experienced clinical exacerbation, seizure, severe encephalopathy, and consequent infantile death (< 1 year). The patient of this study had never had seizure, which could be a potential explanation for the observed mild clinical picture, chronic state, and long-term survival until the age of seven. This study reported the first VWM due to EIF2B gene deficiency with antenatal-onset but mild symptoms and long-term survival. The result of this study showed that stressor factors, particularly seizure, could have a substantial role in poor prognosis and early neonatal death.
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Acknowledgements
We would like to express our special thanks to our patients, their family, medical genetics lab GENEAZMA, and Isfahan University of Medical Science for their collaboration.
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The project was supported by deputies of research of Isfahan University of Medical Sciences [194068].
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MK contributed in data analysis and interpretation, drafted and revised the manuscript. EK contributed in manuscripts writing and laboratory works. MR contributed in data collection and laboratory works. AH: contributed in data analysis and interpretation. OI and OY supervised the clinical evaluation. MR contributed in clinical evaluation. VY contributed in data collection and manuscript revision. MAK designed and supervised the study. All of the authors read and approved the final manuscript to be published and agreed to be responsible for the accuracy of the data and details.
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The study was approved by the Ethical Committee of the Isfahan University of Medical Science (IR.MUI.MED.REC.1398.186).
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Khorrami, M., Khorram, E., Yaghini, O. et al. Identification of a Missense Variant in the EIF2B3 Gene Causing Vanishing White Matter Disease with Antenatal-Onset but Mild Symptoms and Long-Term Survival. J Mol Neurosci 71, 2405–2414 (2021). https://doi.org/10.1007/s12031-021-01810-0
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DOI: https://doi.org/10.1007/s12031-021-01810-0