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 EIF2B5 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 weeks 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 PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A 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.

中文翻译：

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两个兄弟姐妹中EIF2B相关疾病的胎儿发作：小脑发育不全伴无Bergmann胶质细胞和严重髓鞘发育不足。

EIF2B家族基因中的双等位基因致病变异是导致儿童共济失调的中枢神经系统催眠/白质消失，这是中枢白质的进行性神经退行性疾病。迄今为止，仅报告了7例经分子生物学证实的产前发作病例。我们首次报告了从两个胎儿中获得的神经病理学发现，这些胎儿具有EIF2B5基因的有害变体，这些胎儿以子宫发育迟缓和小头畸形的形式出现了子宫内发育迟缓和小头畸形，导致在妊娠27和32周时医学终止妊娠。神经病理学检查证实小头畸形伴迟发性旋转，室周假性囊肿和严重的小脑发育不全。从组织学上讲，小脑皮质不成熟，齿状细胞核碎裂，髓磷脂染色显示下腹结构几乎没有髓鞘形成。Bergmann胶质细胞实际上与小脑白质中成熟星形胶质细胞的数量急剧减少，多个巢蛋白阳性未成熟星形胶质细胞以及PDGRFα阳性少突胶质细胞前体的数量增加有关。在两个胎儿及其父母中进行的全外显子组测序允许在两个胎儿中鉴定出两个EIF2B5化合物杂合变体：c.468C> G p.Ile156Met和c.1165G> A p.Val389Met，父母是杂合子携带者。这些变异在基因组聚合数据库（gnomAD r2.0.2）中不存在。与已经在患有CACH综合征的患者中描述的变体Ile156Met相反，变体p。Val389Met是新颖的，并且使用几种软件预计会有害。神经病理学发现进一步扩大了该疾病的表型谱，该谱表谱很可能发生在妊娠早期，并且可能在妊娠后半年开始出现，严重损害了大脑和小脑的发育。