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The Spectrum of GRIN2A-Associated Disorders

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The Spectrum of GRIN2A-Associated Disorders The Spectrum of GRIN2A-Associated Disorders Vincent Strehlow, Henrike O. Heyne and Johannes R. Lemke Institute of Human Genetics, University Hospital of Leipzig, Germany Summary Schlüsselwörter: Rolando-Epilepsie, Landau-Kleffner- Alterations of the N-methyl-D-aspartate (NMDA) re- Syndrom, CSWS, epileptische Enzephalopathie ceptor subunit GluN2A, encoded by the gene GRIN2A, have been associated with a spectrum of neurodevel- opmental and epilepsy disorders comprising epileptic Le spectre des troubles associés à GRIN2A encephalopathy such as Landau-Kleffner syndrome (LKS) and epilepsy with continuous spikes and waves Des altérations de la sous-unité du récepteur N-mé- during slow-wave sleep (CSWS) as well as less severe thyl-D-aspartate (NMDA) GluN2A, codée par le gène epilepsy disorders such as typical or atypical Rolandic GRIN2A, sont associées à un spectre clinique allant des epilepsy. These disorders do not only share a common troubles du développement neurologique à diverses underlying pathophysiology but also show phenotypic épilepsies, celles-ci incluant de véritables encéphalo- similarities, such as affection of speech development pathies épileptiques (comme le syndrome de Landau- and centro-temporal EEG abnormalities. Kleffner, et l‘épilepsie avec POCS) ainsi que des formes In the present article, we aim to review what is moins graves (comme l’épilepsie rolandique). Ces mala- known so far on GRIN2A-associated epilepsy disorders dies ne partagent pas seulement une physiopatholo- by focusing on genotype-phenotype correlations as gie similaire, mais également des phénotypes qui se well as on functional consequences of mutations. recoupent, en particulier sur le plan de l‘affection du langage et de l’EEG avec pointes pouvant prédominer Epileptologie 2015; 32: 147 – 151 dans les régions centro-temporales. Dans cet article, nous vous donnons un aperçu de Keywords: Rolandic epilepsy, Landau-Kleffner syn- l’état des connaissances sur les épilepsies associées au drome, CSWS, epileptic encephalopathy gène GRIN2A, en nous concentrant sur les corrélations génotype-phénotype et sur les conséquences fonction- nelles des mutations. Das Spektrum GRIN2A-assoziierter Erkrankungen Mots clés : Epilepsie Rolandique, syndrome de Landau- Mutationen der N-Methyl-D-Aspartat (NMDA) Kleffner, CSWS, encéphalopathie épileptique Rezeptoruntereinheit GluN2A, welche durch das Gen GRIN2A kodiert wird, werden mit einem breiten Spektrum von neurologischen Entwicklungsstörungen Structure of the NMDA receptor und Epilepsieerkrankungen inklusive epileptischer En- zephalopathien wie etwa Landau-Kleffner-Syndrom NMDA receptors are ligand-gated ion channels per- (LKS) oder Epilepsie mit kontinuierlichen „Spikes and meable to Na+, K+ and Ca2+ composed of two glycine- Waves“ während des „slow-wave“-Schlafs (CSWS) so- binding GluN1 subunits and two glutamate-binding wie milderen Epilepsieerkrankungen wie der Rolando- GluN2/3 subunits (GluN2A, GluN2B, GluN2C, GluN2D, Epilepsie assoziiert. Diese Erkrankungen teilen nicht GluN3A, GluN3B) resulting in either di- or tri-hetero- nur eine gemeinsam zugrunde liegende Pathophysio- tetrameric ion channels [1, 2]. logie, sondern zeigen zudem phänotypische Ähnlich- All subunits share a similar structure containing keiten wie etwa Sprachentwicklungsstörungen und analogous domains (Figure 1): zentrotemporale EEG-Auffälligkeiten. - an extracellular amino-terminal domain (NTD) con- In der vorliegenden Arbeit möchten wir einen Über- taining binding sites for subtype specific allosteric blick über den derzeitigen Kenntnisstand zu GRIN2A- modulators (e.g. Zn2+) assoziierten Epilepsien geben und dabei auf Geno- - an extracellular ligand-binding domain (LBD) bind- typ-Phänotyp-Korrelationen und funktionelle Konse- ing agonists (e.g. glutamate, glycine) quenzen der Mutationen eingehen. - a channel pore-forming transmembrane domain The Spectrum of GRIN2A-Associated Disorders | V. Strehlow, H. O. Heyne, J. R. Lemke Epileptologie 2015; 32 147 Figure 1: The structure of the NMDA receptor (TMD) comprising four hydrophobic segments (M1- and febrile and focal seizures in infancy [5]. The EEG 4), with M2 only partially entering the membrane showed centro-temporal spikes in two individuals, with - an intracellular carboxyl-terminal domain (CTD) as- one individual being diagnosed with CSWS. The second sociating with postsynaptic density proteins medi- family carried a chromosomal translocation disrupt- ating intracellular signalling ing GRIN2A resulting in diffuse EEG abnormalities and tonic-clonic seizures starting in infancy and persisting The receptor is characterised by relatively slow cur- to youth or early adulthood. rent kinetics, a voltage-dependent block by extracellu- Lesca et al. 2012 investigated a cohort of patients lar Mg2+ and high Ca2+ permeability [3]. It has a specific with epileptic encephalopathies of the LKS and CSWS spatio-temporal expression pattern and is involved in spectrum and revealed an LKS patient (without electri- brain development, plasticity as well as learning and cal status epilepticus during slow-wave sleep) carrying other higher cognitive functions. a microdeletion disrupting GRIN2A [6]. One year later, three groups reported simultaneously on their obser- vation of de novo mutations in GRIN2A as well as rare Spectrum of GRIN2A-associated phenotypes inherited variants in patients of the epilepsy-aphasia spectrum [7 - 9]. Lesca et al. 2013 identified muta- Reutlinger et al. 2010 were the first to assign tions in GRIN2A in about 20% of individuals present- GRIN2A alterations to neurodevelopmental pheno- ing with a clinical phenotype of LKS and/or CSWS as types [4]. They identified different microdeletions on well a atypical benign partial epilepsy (ABPE) [9]. Many 16p13 in three individuals with intellectual disability cases derived from larger families where the mutation (ID), dysmorphic features and epilepsy. All three indi- segregated with a broad range of phenotypes, compris- viduals had a centrotemporal EEG focus. The minimal ing benign childhood epilepsy, absence epilepsy, cen- region of overlap of the three microdeletions contained trotemporal spikes on EEG without seizures, dysphasia only one gene: GRIN2A. Shortly thereafter, Endele et and verbal dyspraxia. Carvill et al. 2013 described four al. 2010 identified the de novo mutation p.N615K in families where the respective GRIN2A mutation segre- GRIN2A in a girl with early-onset epileptic encephalo- gated with autosomal dominant rolandic epilepsy with pathy [5]. The girl was described with epileptic spasms speech dyspraxia, LKS, CSWS or intermediate epilepsy- associated with massive myoclonus (onset at 3 months aphasia disorder [7]. Lemke et al. 2013 showed that of age) as well as severe ID. The EEG showed general- nearly 8% of all patients (n=395) with idiopathic focal ised slowing and bilateral independent posterior spikes. epilepsy carried mutations in GRIN2A, encompassing In addition to this de novo case, Endele et al. 2010 de- 5% (13/284) in Rolandic epilepsy (benign epilepsy with scribed two familial cases. In one family, the mutation centrotemporal spikes, BECTS), 14% (5/37) in ABPE, 13% p.Q218* segregated with mild ID or learning disability (3/23) in LKS and 18% (9/51) in CSWS [8]. In this study, 148 Epileptologie 2015; 32 The Spectrum of GRIN2A-Associated Disorders | V. Strehlow, H. O. Heyne, J. R. Lemke several mutations also segregated in the respective tations in GRIN2A, the distribution of mutations along families with varying phenotypes comprising learn- the gene differs from what was expected initially [5, 7 ing disability, focal epilepsy (including Panayiotopou- - 10, 13, 14]. The most likely pathogenic mutations now los epilepsy) and febrile seizures with centrotemporal appear to cluster in or around ligand-binding sites and spikes on EEG. Some mutation carriers showed no clini- transmembrane domains (Figure 2). Surprisingly, this cal abnormalities at all. Thus, the complete phenotypic region was spared from mutations in the description spectrum ranges from clinically normal to severe early- of the first few carriers [8]. Individuals carrying de novo onset epileptic encephalopathy with profound global mutations within this region appear to have a more developmental delay [10]. However, GRIN2A-associated severe and encephalopathic phenotype. However, this epilepsy phenotypes frequently shared a centrotem- observation is based on only a few patients and may be poral EEG focus. On the other hand, mutations or copy influenced by some degree of selection bias as patients number variations of GRIN2A have been excluded with less severe phenotypes are probably less likely to in larger cohorts of either temporal lobe epilepsy or undergo similar extensive genetic testing as patients idiopathic generalized epilepsy [11]. with severe epileptic encephalopathy. Interestingly, a recent study on three GRIN2A families previously reported [7] revealed a life-long persistence of speech abnormalities in mutation car- Spectrum of GRIN2A mutations riers, independent of other developmental or epilepsy phenotypes [12]. The findings comprised imprecise ar- All sorts of mutations have been reported in ticulation (11/11, 100%), impaired pitch (monopitch GRIN2A, comprising missense mutations, truncating 10/11, 91%) and prosody (stress errors 7/11, 64%) as mutations, splice variants and copy number variations. well as hypernasality (7/11, 64%). There was a decrease In the first small subset of patients (n=27) [8], there of vowel duration (8/11, 73%) and repetition
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