PDF(Pubmed)
Abstract：
Introduction: The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the α-globin gene cluster. Haploinsufficiency of NPRL3, either by deletion or a pathogenic variant, is associated with a variable phenotype of focal epilepsy, with or without malformations of cortical development, with known decreased penetrance. Case Description: This work details the diagnostic odyssey of a neurotypical 10-year-old boy who presented at age 2 with unusual nocturnal episodes and a history of microcytic anemia, as well as a review of the existing literature on NPRL3-related epilepsy, with an emphasis on individuals with deletions who also present with α-thalassemia trait. The proband\'s episodes were mistaken for gastroesophageal reflux disease for several years. He had molecular testing for his α-thalassemia trait and was noted to carry a deletion encompassing the regulatory region of the α-thalassemia gene cluster. Following the onset of overt focal motor seizures, genetic testing revealed a heterozygous loss of NPRL3, within a 106 kb microdeletion on chromosome 16p13.3, inherited from his mother. This deletion encompassed the entire NPRL3 gene, which overlaps the regulatory region of the α-globin gene cluster, giving him the dual diagnosis of NPRL3-related epilepsy and α-thalassemia trait. Brain imaging postprocessing showed left hippocampal sclerosis and mid-posterior para-hippocampal focal cortical dysplasia, leading to the consideration of epilepsy surgery. Conclusions: This case underscores the necessity of early and comprehensive genetic assessments in children with epilepsy accompanied by systemic features, even in the absence of a family history of epilepsy or a developmental delay. Recognizing phenotypic overlaps is crucial to avoid diagnostic delays. Our findings also highlight the impact of disruptions in regulatory regions in genetic disorders: any individual with full gene deletion of NPRL3 would have, at a minimum, α-thalassemia trait, due to the presence of the major regulatory element of α-globin genes overlapping the gene\'s introns.
摘要：
简介：NPRL3基因是GATOR1复合体的关键组成部分，负调节mTORC1通路，对神经发生和大脑发育至关重要。NPRL3位于染色体16p13.3上，位于α-珠蛋白基因簇附近。NPRL3的单倍性缺陷，通过缺失或致病变异，与局灶性癫痫的可变表型有关，有或没有皮质发育畸形，已知外显率降低。病例描述：这项工作详细介绍了一个神经典型的10岁男孩的诊断过程，该男孩在2岁时出现了异常的夜间发作和小红细胞性贫血史，以及对NPRL3相关癫痫的现有文献的回顾，重点是也具有α-地中海贫血特征的缺失个体。先证者的发作被误认为胃食管反流病已有数年。他对自己的α-地中海贫血性状进行了分子测试，并指出其带有包含α-地中海贫血基因簇调节区的缺失。在明显的局灶性运动性癫痫发作后，遗传测试显示NPRL3的杂合丢失，在16p13.3染色体上的106kb微缺失内，遗传自他的母亲。这种缺失包括整个NPRL3基因，与α-珠蛋白基因簇的调节区重叠，给他的NPRL3相关的癫痫和α-地中海贫血性状的双重诊断。脑成像后处理显示左侧海马硬化和海马中后段局灶性皮质发育不良，导致癫痫手术的考虑。结论：该病例强调了对伴有系统性特征的癫痫患儿进行早期和全面的基因评估的必要性。即使没有癫痫家族史或发育迟缓。识别表型重叠对于避免诊断延迟至关重要。我们的发现还强调了遗传疾病中调控区域中断的影响：任何具有NPRL3全基因缺失的个体都会有，至少,α-地中海贫血性状，由于α-珠蛋白基因与基因内含子重叠的主要调节元件的存在。
