Abstract：
N-methyl-D-aspartate receptors (NMDAR) are ligand-gated ion channels mediating excitatory neurotransmission and are important for normal brain development, cognitive abilities, and motor functions. Pathogenic variants in the Glutamate receptor Ionotropic N-methyl-D-aspartate (GRIN) genes (GRIN1, GRIN2A-D) encoding NMDAR subunits have been associated with a wide spectrum of neurodevelopmental disorders and epilepsies ranging from treatable focal epilepsies to devastating early-onset developmental and epileptic encephalopathies. Genetic variants in NMDA receptor genes can cause a range of complex alterations to receptor properties resulting in various degrees of loss-of-function, gain-of-function, or mixtures thereof. Understanding how genetic variants affect the function of the receptors, therefore, represents an important first step in the ongoing development towards targeted therapies. Currently, targeted treatment options for GRIN-related diseases are limited. However, treatment with memantine has been reported to significantly reduce seizure frequency in a few individuals with developmental and epileptic encephalopathies harboring de novo gain-of-function GRIN2A missense variants, and supplementary treatment with L-serine has been associated with improved motor and cognitive performance as well as reduced seizure frequency in patients with GRIN2B loss-of-function missense variants as well as GRIN2A and GRIN2B null variants.
摘要：
N-甲基-D-天冬氨酸受体（NMDAR）是介导兴奋性神经传递的配体门控离子通道，对正常的大脑发育很重要，认知能力,和电机功能。编码NMDAR亚基的谷氨酸受体离子型N-甲基-D-天冬氨酸（GRIN）基因（GRIN1，GRIN2A-D）的致病变体与广泛的神经发育障碍和癫痫相关，范围从可治疗的局灶性癫痫到破坏性的早发性癫痫和癫痫性脑病。NMDA受体基因的遗传变异可引起一系列复杂的受体特性改变，导致不同程度的功能丧失。函数增益，或其混合物。了解遗传变异如何影响受体的功能，因此,代表了正在进行的靶向治疗发展的重要的第一步。目前,GRIN相关疾病的靶向治疗方案有限.然而,据报道，用美金刚治疗可显著降低少数患有从头功能获得GRIN2A错义变异的发育性和癫痫性脑病的个体的癫痫发作频率，在具有GRIN2B功能丧失错义变异体以及GRIN2A和GRIN2B无效变异体的患者中,L-丝氨酸的补充治疗与运动和认知表现的改善以及癫痫发作频率的降低相关.
