Department of Pathology, Universitair Ziekenhuis Brussel, Brussels, Belgium
Neurogenetics Research Group, Reproduction Genetics and Regenerative Medicine Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium.
J Med Genet. 2023 Feb;60(2):183-192. doi: 10.1136/jmedgenet-2021-107971. Epub 2022 Apr 7.
Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in or , genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.
We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in .
Heterozygous variants in and were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous variants in an individual with microcephaly with simplified gyral pattern.
These findings expand our understanding of the clinical and imaging features of the 'NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.
在编码 N-甲基-D-天冬氨酸受体（NMDAR）亚基的 或 基因的杂合致病性变异的一部分患者中，已经报道了皮质发育畸形（MCD）。本研究的目的是进一步定义与 NMDAR 相关的 MCD 的表型谱。
我们报告了 7 名新患者的临床、放射学和分子特征，并回顾了 18 名先前报道的具有与 NMDAR 相关的 MCD 的个体的数据。介绍了两个具有 杂合变异的个体的神经病理学发现。我们报告了一个具有 纯合致病性变异的个体的临床和神经病理学特征。
和 中的杂合变体与重叠的严重临床和影像学特征相关，包括全面发育迟缓、癫痫、弥漫性发育不良、形态异常的基底节和海马。两个具有 杂合变异的胎儿的神经病理学检查表明，增殖以及放射状和切线神经元迁移均受损。此外，我们还表明，在一个具有简单脑回模式的小头畸形个体中，纯合 变体也会损害神经元迁移。
这些发现扩展了我们对“NMDARopathy”谱的临床和影像学特征的理解，并有助于我们理解这些患者中导致 MCD 的潜在致病机制。
