Department of Medical Genetics, Bordeaux University Hospital, Bordeaux, France.
Bordeaux Univ, INSERM U1211, Bordeaux University Hospital, Bordeaux, France.
Acta Neuropathol Commun. 2020 Apr 15;8(1):48. doi: 10.1186/s40478-020-00929-2.
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.
EIF2B 家族基因的双等位致病性变异可导致儿童脑性共济失调伴中枢神经系统脑白质发育不良/脑白质消失症，这是一种中枢白质进行性神经退行性疾病。迄今为止，仅报道了 7 例具有产前发病的分子确诊病例。我们首次报道了两个胎儿的神经病理学发现，这两个胎儿携带 EIF2B5 基因的有害变异，在宫内生长迟缓且头围小，脑回模式简化，导致妊娠在 27 周和 32 周时终止。神经病理学检查证实为小头畸形伴脑回发育延迟、脑室周围假囊肿和严重小脑发育不良。组织学上，小脑皮质不成熟，齿状核碎裂，髓鞘染色显示下脑结构几乎没有髓鞘形成。Bergmann 胶质细胞几乎不存在，小脑白质中成熟星形胶质细胞数量急剧减少，巢蛋白阳性幼稚星形胶质细胞增多，PDGRFα 阳性少突胶质细胞前体细胞增多。对这两个胎儿及其父母进行全外显子组测序，在两个胎儿中发现了 EIF2B5 复合杂合变异：c.468C > G p.Ile156Met 和 c.1165G > A p.Val389Met，父母为杂合携带者。这些变异在基因组聚集数据库（gnomAD r2.0.2）中不存在。与已在 CACH 综合征患者中描述的变异 Ile156Met 相反，p.Val389Met 是新的，并且使用多种软件预测为有害。神经病理学发现进一步扩展了疾病的表型谱，该病很可能发生在妊娠早期，并可能在妊娠后半期因大脑和小脑发育严重受损而表现出来。
