Abdel-Hamid Mohamed S, Abdel-Ghafar Sherif F, Sayed Inas S M, Zaki Maha S, Abdel-Salam Ghada M H
Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Orodental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Clin Genet. 2025 Aug;108(2):184-193. doi: 10.1111/cge.14720. Epub 2025 Feb 18.
Cystatin B gene (CSTB) is responsible for the most common childhood onset type of progressive myoclonic epilepsy (EPM1A). More recently, biallelic CSTB variants were described in four patients with a neonatal onset phenotype of microcephaly, diffuse hypomyelination, brain atrophic changes, and dyskinesia. Herein, we describe the clinical and molecular characterization of five additional patients in whom exome sequencing detected a splice variant (c.67-1G>C) in Family I and II and a missense variant (c.10G>C, p.Gly4Arg) in Family III and IV. Interestingly, these variants were described before in patients with EPM1A. However, all our patients had progressive microcephaly, developmental delay, and dyskinesia. In addition, only one patient developed seizures. Brain imaging showed mainly diffuse hypomyelination and progressive cerebral and cerebellar atrophy of variable severity. Interestingly, one patient showed intracranial calcification and another showed congenital distal arthrogryposis. Our findings support the association between CSTB variants and the neonatal form as a distinct neurodevelopmental phenotype. This newly characterized neonatal onset of the CSTB shares many overlapping features with genetic disorders encompassing microcephaly and hypomyelination.
胱抑素B基因（CSTB）是导致最常见的儿童期起病的进行性肌阵挛癫痫（EPM1A）的原因。最近，在4例患有小头畸形、弥漫性髓鞘形成不良、脑萎缩性改变和运动障碍新生儿起病表型的患者中描述了双等位基因CSTB变异。在此，我们描述了另外5例患者的临床和分子特征，其中外显子组测序在I和II家族中检测到一个剪接变异（c.67-1G>C），在III和IV家族中检测到一个错义变异（c.10G>C，p.Gly4Arg）。有趣的是，这些变异之前在EPM1A患者中已有描述。然而，我们所有的患者都有进行性小头畸形、发育迟缓及运动障碍。此外，只有1例患者出现癫痫发作。脑成像主要显示弥漫性髓鞘形成不良以及不同严重程度的进行性大脑和小脑萎缩。有趣的是，1例患者显示颅内钙化，另1例显示先天性远端关节挛缩。我们的研究结果支持CSTB变异与作为一种独特神经发育表型的新生儿形式之间的关联。这种新特征化的CSTB新生儿起病与包括小头畸形和髓鞘形成不良的遗传性疾病有许多重叠特征。
