Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs

Stülpnagel, Celina von; Ensslen, Matthias; Møller, Rikke S.; Pal, Deb K.; Masnada, Silvia; Veggiottì, P.; Piazza, E.; Dreesmann, Mona; Hartlieb, Till; Herberhold, T.; Hughes, Elaine; Koch, Maximilian; Kutzer, Christina; Hoertnagel, Konstanze; Nitanda, J; Pohl, Michael; Rostásy, Kevin; Haack, Tobias B.; Stöhr, Katharina; Kluger, Gerhard; Borggraefe, Ingo

doi:10.1016/j.ejpn.2017.01.001

Cited by 37 publications

(19 citation statements)

References 30 publications

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“…Twelve distinct de novo missense variants within the sequence encoding the M2 pore loop in NMDAR GRIN genes were identified in 18 probands with neurological and neuropsychiatric conditions (Table , Table S1; Figure ). These include three GRIN1 variants with one variant leading to GluN1‐p.G618R and two distinct variants (c.1858G>C and c.1858G>A) leading to the same amino‐acid change GluN1‐p.G620R identified in two unrelated patients with developmental delay/intellectual disability and hypotonia (Chen et al, ; Lemke et al, ), three GRIN2A variants corresponding to GluN2A‐p.L611Q, GluN2A‐p.N614S, and GluN2A‐p.N615K found in patients with epilepsy, developmental delay/intellectual disability, autism, and/or speech disorder (Allen et al, ; Endele et al, ; Farwell et al, ; Strehlow et al, ; von Stülpnagel et al, ), and seven GRIN2B variants encoding GluN2B‐p.W607C, GluN2B‐p.G611V, GluN2B‐p.N615I, GluN2B‐p.N615K, GluN2B‐p.N616K, GluN2B‐p.V618G, and GluN2B‐p.V620M found in patients with developmental delay/intellectual disability, and/or epilepsy, and/or autism spectrum disorders (Lemke et al, ; Platzer et al, ; Retterer et al, ; Yavarna et al, ). All 18 patients showed a degree of intellectual disability or developmental delay.…”

Section: Resultsmentioning

confidence: 99%

De novoGRINvariants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases

Zhang

Tang

et al. 2019

Human Mutation

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N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single-channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge

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Section: Resultsmentioning

confidence: 99%

De novoGRINvariants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases

Zhang

Tang

et al. 2019

Human Mutation

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“…For 10 of the 25 patients (40%) with a (likely) pathogenic variant, the new diagnosis might have, according to the literature, a consequence for antiepileptic treatment …”

Section: Discussionmentioning

confidence: 99%

“…There is also literature suggesting that patients with SCN8A gain of function mutations have been shown to respond well to high‐dose phenytoin . In addition, there is literature suggesting that for some patients with a GRIN2A missense mutation, the N ‐methyl‐ d ‐aspartate receptor blocker memantine should be considered and that finding a mutation in the CACNA1A, …”

Section: Discussionmentioning

confidence: 99%

Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability

Snoeijen‐Schouwenaars

Ool

Verhoeven

et al. 2018

Epilepsia

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Objective: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. Methods: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. Results: In 58 patients, the diagnostic WES analysis reported one or more variant(s).In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. Significance: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. K E Y W O R D S genetic diagnosis, learning disability, next generation sequencing, seizures

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“…Identification of GRIN2A mutations in BECTS and other childhood epilepsies has thrown light on the role of GluN2A subunit-containing NMDARs in epilepsy (Lemke et al, 2013 ; Gao et al, 2017 ; Von Stülpnagel et al, 2017 ). Recent findings indicate that GRIN2A mutations prolong NMDARs' deactivation time, decrease the amplitude of current responses, reduce glutamate potency, reduce channel open probability and accentuate the sensitivity of NMDARs toward negative allosteric modulators (Gao et al, 2017 ; Sibarov et al, 2017 ).…”

Section: Future Recommendationsmentioning

confidence: 99%

Sleep Related Epilepsy and Pharmacotherapy: An Insight

et al. 2018

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In the last several decades, sleep-related epilepsy has drawn considerable attention among epileptologists and neuroscientists in the interest of new paradigms of the disease etiology, pathogenesis and management. Sleep-related epilepsy is nocturnal seizures that manifest solely during the sleep state. Sleep comprises two distinct stages i.e., non-rapid eye movement (NREM) and rapid eye movement (REM) that alternate every 90 min with NREM preceding REM. Current findings indicate that the sleep-related epilepsy manifests predominantly during the synchronized stages of sleep; NREM over REM stage. Sleep related hypermotor epilepsy (SHE), benign partial epilepsy with centrotemporal spikes or benign rolandic epilepsy (BECTS), and Panayiotopoulos Syndrome (PS) are three of the most frequently implicated epilepsies occurring during the sleep state. Although some familial types are described, others are seemingly sporadic occurrences. In the present review, we aim to discuss the predominance of sleep-related epilepsy during NREM, established familial links to the pathogenesis of SHE, BECTS and PS, and highlight the present available pharmacotherapy options.

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Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs

Cited by 37 publications

References 30 publications

De novoGRINvariants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases

De novoGRINvariants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases

Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability

Sleep Related Epilepsy and Pharmacotherapy: An Insight

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