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Proband and neuroimaging. (A) The proband was nondysmorphic. (B–D) MRI of the brain at 9 years of age (B-Axial T1, C-Sagittal T1, D-Axial FLAIR) showed progressive cerebral atrophy and a thin corpus callosum associated with subtle abnormalities of the white matter including hypomyelination of the terminal zones and the temporal lobes.
Source publication
Objective
Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband. Methods
Three modern translational medici...
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N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brai...
Citations
... The ultimate goal of all genetic research and diagnostics is the identification of pathogenetically relevant changes that allow for improved and targeted treatment in the sense of precision medicine. For GRIN2A-related epilepsy with GOF mutations, great hopes were therefore pinned on treatment with the NMDA receptor antagonist memantine, after an initial case report described clearly positive effects of this drug [22]. Unfortunately, confirmatory studies provide only limited support for therapeutic decisions, which means that the treatment success of individual cases is of little significance. ...
Self-limiting focal epilepsies are among the most common forms of epilepsy in children. Based on family studies, a genetic basis is assumed for the epilepsy as well as the typical electroencephalographic (EEG) feature of centrotemporal spikes, although complex inheritance and possibly additional influencing factors must be considered. Variants in GRIN2A , encoding the GluN2A subunit of the N‑methyl-D-aspartate (NMDA) glutamate receptor, represent the most important genetic risk factor to date. With memantine for variants with a gain-of-function effect and L‑serine for loss-of-function variants, two personalized therapeutic approaches are potentially available. Their effectiveness and significance need to be clarified in further investigations and clinical trials.
... and cost-effectiveness, surpassing older technologies (14,15). Exome sequencing (ES) has played a crucial role in identifying previously unknown diseases as rare diseases (16,17). ...
With the development of clinical experience and technology, rare diseases (RDs) are gradually coming into the limelight. As they often lead to poor prognosis, it is urgent to promote the accuracy and rapidity of diagnosis and promote the development of therapeutic drugs. In recent years, with the rapid improvement of single-cell sequencing technology, the advantages of multi-omics combined application in diseases have been continuously explored. Single-cell metabolomics represents a powerful tool for advancing our understanding of rare diseases, particularly metabolic RDs, and transforming clinical practice. By unraveling the intricacies of cellular metabolism at a single-cell resolution, this innovative approach holds the potential to revolutionize diagnosis, treatment, and management strategies, ultimately improving outcomes for RDs patients. Continued research and technological advancements in single-cell metabolomics are essential for realizing its full potential in the field of RDs diagnosis and therapeutics. It is expected that single-cell metabolomics can be better applied to RDs research in the future, for the benefit of patients and society.
... 6 There is limited evidence of visible subcortical and cortical anomalies. Individuals may show brain atrophy (11% 6 ) while others show regional cortical dysplasia, reduced corpus callosum, or hippocampal sclerosis (e.g., a few cases in the study by Strehlow et al. 6 ; see the study by Pierson et al. 9 for a case with general hypomyelination at age 9 years). It is noteworthy that MRI profiles may also depend on genotypes 6 and that milder gain-of-function variations are linked to milder phenotypes. ...
Background and Objectives
Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development.
Methods
We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared.
Results
Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η² = 0.37) than the right (η² = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences.
Discussion
Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A-related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.
... For patients of drug-resistant epilepsy with GRIN gene variants, FDA-approved NMDAR blockers might provide some reduction in excitation and possibly epileptiform activity, with potential utility as antiseizure medications [43,48,51,52]. The evaluation of FDA-approved NMDAR channel blockers suggests that most of the GoF M3 variant NMDARs decreased the sensitivity to ketamine, memantine, dextrorphan and dextromethorphan, suggesting that these drugs are unlikely to be suitable for patients with certain GRIN variants, since the drugs do not reach levels in brain necessary to block variant NMDARs. ...
N-methyl-d-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure–function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.
... änderungen, die eine verbesserte und zielgerichtete Therapie im Sinne einer Präzisionsmedizin erlauben. Für GRIN2A-assoziierte Epilepsien mit GOF-Mutationen lagen daher große Hoffnungen auf einer Therapie mit dem NMDA-Rezeptorantagonisten Memantin, nachdem ein erster Fallberichte deutlich positive Effekte der Substanz beschrieben hatte [22]. Leider fehlen bis heute bestätigende Studien, die Behandlungserfolge des Einzelfalls sind damit kaum aussagekräftig. ...
Zusammenfassung
Selbstlimitierende fokale Epilepsien gehören zu den häufigsten Epilepsieformen im Kindesalter. Basierend auf Familienstudien für die Epilepsie wie auch das typische Elektroenzephalogramm (EEG-)Merkmal der „centrotemporal spikes“ wird eine genetische Grundlage angenommen, wobei von einer komplexen Vererbung sowie möglicherweise zusätzlichen Einflussfaktoren ausgegangen werden muss. Varianten in GRIN2A , kodierend für die GluN2A-Untereinheit des NMDA-Glutamat-Rezeptors (N-Methyl-D-Aspartat), stellen den bisher wichtigsten genetischen Risikofaktor da. Mit Memantin für Varianten mit Gain-of-function-Effekt und L‑Serin für Loss-of-function-Varianten stehen potenziell zwei personalisierte Therapieansätze zur Verfügung, deren Wirksamkeit und Bedeutung in weiteren Untersuchungen und Therapiestudien zu klären ist.
... Rather, these data suggest that in vitro analysis of channel blocker potency should identify candidate blockers for potential testing for off-label use in patients or future clinical trials with variants that are identified unambiguously to produce a gain-of-function (e.g., Myers et al., 2023). In some cases, missense variants alter the residues within the pore to render channel blockers more potent at the variant (e.g., Pierson et al., 2014;Xu et al., 2021), and in these situations, one might expect improvement in clinical phenotype for gain-of-function variants since channel blocking drugs will reduce aberrant activity through variant receptors to a greater extent than activity through WT receptors. ...
N-methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re-entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage-dependent Mg2+ inhibition. Voltage-dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3-dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA-approved NMDAR drugs-memantine, dextromethorphan, and ketamine-were chosen based on their ability to bind near the M2 re-entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage-dependent Mg2+ block. These results provide insight of structural determinants of FDA-approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology.
... To achieve symptomatic benefit for chorea, high doses of amantadine were required. Amantadine shown intolerable side effects such as hallucinations, confusion, insomnia, sleepiness, agitation, and anxiety at high dose [56,57]. Riluzole inhibits NMDARs by acting as a GluN2B antagonist. ...
... Log D values of these analogues were in the good range for penetration of blood-brain barrier to reach CNS [55 (Log D = 1.68), methyl ether (56, Log D = 2.46) and benzyl ether (57, Log D = 4.14)]. Benzyl ether (57) has shown the highest Log D value. Moreover, Log D value for well-known GluN2B antagonist (Ifenprodil) was described for the first time (Log D = 1.49). ...
N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure–function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.
Graphical abstract
... However, the drug has been removed from market due to adverse side effects observed in patients. More recently, gabapentin has been found to be a potent activator of M-current, making it a possible drug candidate for KCNQ2/3-related epilepsy [24]. ...
Epilepsy is a common and debilitating neurological disease with a significant genetic component. Inherited or de novo mutations in ion channels resulting in periodic network hyperexcitability is a major cause of epileptogenesis. Understanding of the genetic etiology of epilepsy opens up the avenue of personalized treatment. A range of precision medications are designed to target the defective ion channels, with varied effects. In addition, the underlying mechanisms of channelopathies can also be addressed by gene therapy. Expression of mutated ion channel genes can be regulated via gene replacement or gene silencing approaches, including viral vector-mediated gene replacement and antisense oligonucleotides. Aside from directly compensating of ion channel dysfunction, another strategy of gene therapy involves the overexpression of certain ion channels to modulate neuronal excitability, which particularly targets focal epilepsies. In line with the paroxysmal nature of epileptic seizures, optogenetic and chemogenetic approaches, which permits conditional activation of gene products can be particularly beneficial. The ideal gene therapy to treat genetic epilepsies and channelopathies would be in vivo gene editing, making precise gene modifications to correct mutations harbored by each individual. Advances in CRISPR- Cas technology has brought the idea closer to reality, yet technical and ethical concerns surround its therapeutic application.
... Regarding GRIN2A mutation-related epileptic encephalopathy, memantine was reported to have decreased the frequency and onset of seizures in a 3-year-old boy with heterozygous c.1083G > A (p.Leu361 =) variant in GRIN2A [218]. In a de novo missense mutation (c.2434C > A; p.L812M) patient, add-on memantine reduced seizure burden and improved interictal EEG [219]. However, we have not yet known whether memantine is effective in all of these patient populations. ...
Glutamate is an essential excitatory neurotransmitter in the central nervous system, playing an indispensable role in neuronal development and memory formation. The dysregulation of glutamate receptors and the glutamatergic system is involved in numerous neurological and psychiatric disorders, especially epilepsy. There are two main classes of glutamate receptor, namely ionotropic and metabotropic (mGluRs) receptors. The former stimulate fast excitatory neurotransmission, are N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate; while the latter are G-protein-coupled receptors that mediate glutamatergic activity via intracellular messenger systems. Glutamate, glutamate receptors, and regulation of astrocytes are significantly involved in the pathogenesis of acute seizure and chronic epilepsy. Some glutamate receptor antagonists have been shown to be effective for the treatment of epilepsy, and research and clinical trials are ongoing.
... It is a derivative of an antiviral component amantadine and consists of 3 ring structure along with two methyl groups and one amine group (Fig. 3) [107]. Relative to other NMDA antagonists, memantine possess lower affinity, avoids prolonged cohesion toward receptor and is well tolerated, and thus can be used for the treatment of AD at different stages [108,109]. Among others, it prevents the excitotoxicity mediated by NMDA receptor and shows stronger functional voltage dependency and faster kinetics relative to other high affinity antagonists [42,110]. ...
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