{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:08:28Z","timestamp":1790064508617,"version":"4.0.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T00:00:00Z","timestamp":1586908800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T00:00:00Z","timestamp":1586908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination\/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the\n                    <jats:italic>EIF2B5<\/jats:italic>\n                    gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32\u2009weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRF\u03b1-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two\n                    <jats:italic>EIF2B5<\/jats:italic>\n                    compound heterozygous variants in the two foetuses: c.468C\u2009&gt;\u2009G p.Ile156Met and c.1165G\u2009&gt;\u2009A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.\n                  <\/jats:p>","DOI":"10.1186\/s40478-020-00929-2","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T08:02:37Z","timestamp":1586937757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination"],"prefix":"10.1186","volume":"8","author":[{"given":"Aur\u00e9lien","family":"Trimouille","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Marguet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Sauvestre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eulalie","family":"Lasseaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Pelluard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Laure","family":"Martin-N\u00e9grier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Plaisant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Rooryck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Lacombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beno\u00eet","family":"Arveiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odile","family":"Boespflug-Tanguy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Naudion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Laquerri\u00e8re","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,15]]},"reference":[{"key":"929_CR1","doi-asserted-by":"publisher","unstructured":"Van der Knaap MS, Barth PG, Gabre\u00ebls FJ, Franzoni E, Begeer JH, Stroink H et al (1997) A new leukoencephalopathy with vanishing white matter. Neurology. 48:845\u2013 55. https:\/\/doi.org\/10.1212\/wnl.48.4.845","DOI":"10.1212\/wnl.48.4.845"},{"key":"929_CR2","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/ng764","volume":"29","author":"PA Leegwater","year":"2001","unstructured":"Leegwater PA, Vermeulen G, K\u00f6nst AA, Naidu S, Mulders J, Visser A et al (2001) Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 29:383\u2013388. https:\/\/doi.org\/10.1038\/ng764","journal-title":"Nat Genet"},{"key":"929_CR3","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1212\/WNL.0b013e3181f962ae","volume":"75","author":"HDW Van der Lei","year":"2010","unstructured":"Van der Lei HDW, van Berkel CGM, van Wieringen WN, Brenner C, Feigenbaum A, Mercimek-Mahmutoglu S et al (2010) Genotype-phenotype correlation in vanishing white matter disease. Neurology. 75:1555\u20131559. https:\/\/doi.org\/10.1212\/WNL.0b013e3181f962ae","journal-title":"Neurology."},{"key":"929_CR4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1097\/NEN.0b013e318203ae74","volume":"70","author":"M Bugiani","year":"2011","unstructured":"Bugiani M, Boor I, van Kollenburg B, Postma N, Polder E, van Berkel C et al (2011) Defective glial maturation in vanishing white matter disease. J Neuropathol Exp Neurol 70:69\u201382. https:\/\/doi.org\/10.1097\/NEN.0b013e318203ae74","journal-title":"J Neuropathol Exp Neurol"},{"key":"929_CR5","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/mrdd.20104","volume":"12","author":"JC Pronk","year":"2006","unstructured":"Pronk JC, van Kollenburg B, Scheper GC, van der Knaap MS (2006) Vanishing white matter disease: a review with focus on its genetics. Ment Retard Dev Disabil Res Rev 12:123\u2013128. https:\/\/doi.org\/10.1002\/mrdd.20104","journal-title":"Ment Retard Dev Disabil Res Rev"},{"key":"929_CR6","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","volume":"46","author":"M Kircher","year":"2014","unstructured":"Kircher M, Witten DM, Jain P, O\u2019Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310\u2013315. https:\/\/doi.org\/10.1038\/ng.2892","journal-title":"Nat Genet"},{"key":"929_CR7","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/humu.10212","volume":"21","author":"PD Stenson","year":"2003","unstructured":"Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NST et al (2003) Human gene mutation database (HGMD \u00ae ): 2003 update: HGMD 2003 UPDATE. Hum Mutat 21:577\u2013581. https:\/\/doi.org\/10.1002\/humu.10212","journal-title":"Hum Mutat"},{"key":"929_CR8","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1086\/379524","volume":"73","author":"MS Van der Knaap","year":"2003","unstructured":"Van der Knaap MS, van Berkel CGM, Herms J, van Coster R, Baethmann M, Naidu S et al (2003) eIF2B-related disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet 73:1199\u20131207. https:\/\/doi.org\/10.1086\/379524","journal-title":"Am J Hum Genet"},{"key":"929_CR9","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1177\/0883073817712588","volume":"32","author":"H Song","year":"2017","unstructured":"Song H, Haeri S, Vogel H, van der Knaap M, Van Haren K (2017) Postmortem whole exome sequencing identifies novel EIF2B3 mutation with prenatal phenotype in 2 siblings. J Child Neurol 32:867\u2013870. https:\/\/doi.org\/10.1177\/0883073817712588","journal-title":"J Child Neurol"},{"key":"929_CR10","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1111\/bpa.12606","volume":"28","author":"M Bugiani","year":"2018","unstructured":"Bugiani M, Vuong C, Breur M, van der Knaap MS (2018) Vanishing white matter: a leukodystrophy due to astrocytic dysfunction. Brain Pathol 28:408\u2013421. https:\/\/doi.org\/10.1111\/bpa.12606","journal-title":"Brain Pathol"},{"issue":"6","key":"929_CR11","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1093\/jnen\/63.6.618","volume":"63","author":"K Van Haren","year":"2004","unstructured":"Van Haren K, van der Voorn JP, Peterson DR, van der Knaap MS, Powers JM (2004) The life and death of oligodendrocytes in vanishing white matter disease. J Neuropathol Exp Neurol 63(6):618\u2013630. https:\/\/doi.org\/10.1093\/jnen\/63.6.618","journal-title":"J Neuropathol Exp Neurol"},{"issue":"4","key":"929_CR12","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1172\/JCI83908","volume":"126","author":"S Dooves","year":"2016","unstructured":"Dooves S, Bugiani M, Postma NL, Polder E, Land N, Horan ST et al (2016) Astrocytes are central in the pathomechanisms of vanishing white matter. J Clin Invest 126(4):1512\u20131524. https:\/\/doi.org\/10.1172\/JCI83908","journal-title":"J Clin Invest"},{"key":"929_CR13","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1111\/nan.12411","volume":"44","author":"S Dooves","year":"2018","unstructured":"Dooves S, Bugiani M, Wisse LE, Abbink TEM, van der Knaap MS, Heine VM (2018) Bergmann glia translocation: a new disease marker for vanishing white matter identifies therapeutic effects of Guanabenz treatment. Neuropathol Appl Neurobiol 44:391\u2013403. https:\/\/doi.org\/10.1111\/nan.12411","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"6","key":"929_CR14","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1111\/cns.13107","volume":"25","author":"L Zhou","year":"2019","unstructured":"Zhou L, Li P, Chen N et al (2019) Modeling vanishing white matter disease with patient-derived induced pluripotent stem cells reveals astrocytic dysfunction. CNS Neurosci Ther 25(6):759\u2013771. https:\/\/doi.org\/10.1111\/cns.13107","journal-title":"CNS Neurosci Ther"},{"issue":"5","key":"929_CR15","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1002\/ana.25585","volume":"86","author":"PS Leferink","year":"2018","unstructured":"Leferink PS, Dooves S, Hillen AEJ, Marjo S, der Knaap V, Heine VM (2018) Astrocyte subtype vulnerability in stem cell models of vanishing white matter. Ann Neurol 86(5):780\u2013792. https:\/\/doi.org\/10.1002\/ana.25585","journal-title":"Ann Neurol"},{"key":"929_CR16","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/sj.ejhg.5201189","volume":"12","author":"A Fogli","year":"2004","unstructured":"Fogli A, Schiffmann R, Hugendubler L, Combes P, Bertini E, Rodriguez D et al (2004) Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Eur J Hum Genet 12:561\u2013566. https:\/\/doi.org\/10.1038\/sj.ejhg.5201189","journal-title":"Eur J Hum Genet"},{"key":"929_CR17","doi-asserted-by":"publisher","unstructured":"Terumitsu-Tsujita M, Kitaura H, Miura I et al (2019) Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model [published online ahead of print, 2019 Oct 6]. J Neurochem. https:\/\/doi.org\/10.1111\/jnc.14887","DOI":"10.1111\/jnc.14887"},{"key":"929_CR18","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/nm1195","volume":"11","author":"J Dietrich","year":"2005","unstructured":"Dietrich J, Lacagnina M, Gass D, Richfield E, Mayer-Pr\u00f6schel M, Noble M et al (2005) EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med 11:277\u2013283. https:\/\/doi.org\/10.1038\/nm1195","journal-title":"Nat Med"},{"key":"929_CR19","doi-asserted-by":"publisher","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","volume":"44","author":"MJ Landrum","year":"2016","unstructured":"Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S et al (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44:D862\u2013D868. https:\/\/doi.org\/10.1093\/nar\/gkv1222","journal-title":"Nucleic Acids Res"},{"key":"929_CR20","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1177\/0883073807308705","volume":"23","author":"J Maletkovic","year":"2008","unstructured":"Maletkovic J, Schiffmann R, Gorospe JR, Gordon ES, Mintz M, Hoffman EP et al (2008) Genetic and clinical heterogeneity in eIF2B-related disorder. J Child Neurol 23:205\u201315.16. https:\/\/doi.org\/10.1177\/0883073807308705","journal-title":"J Child Neurol"},{"key":"929_CR21","doi-asserted-by":"publisher","unstructured":"Hamilton EMC, van der Lei HDW, Vermeulen G, Gerver JAM, Louren\u00e7o CM, Naidu S et al (2018) Natural history of vanishing white matter: natural history of VWM. Ann Neurol 84:274\u2013288. https:\/\/doi.org\/10.1002\/ana.25287","DOI":"10.1002\/ana.25287"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-020-00929-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-020-00929-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-020-00929-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T19:23:02Z","timestamp":1618428182000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-020-00929-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,15]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["929"],"URL":"https:\/\/doi.org\/10.1186\/s40478-020-00929-2","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,15]]},"assertion":[{"value":"24 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Autopsies and genetic analyses were performed after appropriate informed consent was obtained from the parents who provided informed consent for publication.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors have no competing interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"48"}}