GRIN2A and GRIN2B and Their Related Phenotypes

Abstract

Glutamate is the most relevant excitatory neurotransmitter of the central nervous system; it binds with several receptors, including N-methyl-D-aspartate receptors (NMDARs), a subtype of ionotropic glutamate receptor that displays voltage-dependent block by Mg²⁺ and a high permeability to Ca²⁺. GRIN2A and GRIN2B genes encode the GluN2A and GluN2B subunits of the NMDARs, which play important roles in synaptogenesis, synaptic transmission, and synaptic plasticity, as well as contributing to neuronal loss and dysfunction in several neurological disorders. Recently, individuals with a range of childhood-onset drug-resistant epilepsies, such as Landau–Kleffner or Lennox–Gastaut syndrome, intellectual disability (ID), and other neurodevelopmental abnormalities have been found to carry mutations in GRIN2A and GRIN2B, with high variable expressivity in phenotype. The first one is found mainly in epilepsy-aphasia syndromes, while the second one mainly in autism, schizophrenia, and ID, such as autism spectrum disorders. Brain magnetic resonance imaging alterations are found in some patients, even if without a clear clinical correlation. At the same time, increasing data on genotype–phenotype correlation have been found, but this is still not fully demonstrated. There are no specific therapies for the treatment of correlated NMDARs epilepsy, although some evidence with memantine, an antagonist of glutamate receptor, is reported in the literature in selected cases with mutation determining a gain of function.

Keywords

GRIN2A - GRIN2B - glutamate - epilepsy-aphasia spectrum - Landau–Kleffner syndrome - Lennox–Gastaut syndrome

^* These authors have equally contributed to the present article.

Publikationsverlauf

Eingereicht: 20. Februar 2021

Angenommen: 21. Februar 2021

Artikel online veröffentlicht:
21. Mai 2021

• References

• 1 Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001; 11 (03) 327-335
• 2 Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE 2004; 2004 (255) re16-re16
• 3 Conroy J, McGettigan PA, McCreary D. et al. Towards the identification of a genetic basis for Landau-Kleffner syndrome. Epilepsia 2014; 55 (06) 858-865
• 4 Strehlow V, Heyne HO, Vlaskamp DRM. et al; GRIN2A study group. GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain 2019; 142 (01) 80-92
• 5 Myers KA, Scheffer IE. GRIN2A-Related Speech Disorders and Epilepsy. 2016. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020
• 6 Lemke JR, Hendrickx R, Geider K. et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol 2014; 75 (01) 147-154
• 7 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A [phone]
• 8 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
• 9 Brancati F, Travaglini L, Zablocka D. et al; International JSRD Study Group. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 2008; 74 (02) 164-170
• 10 Adams DR, Yuan H, Holyoak T. et al. Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. Mol Genet Metab 2014; 113 (03) 161-170
• 11 Allen NM, Conroy J, Shahwan A. et al. Unexplained early onset epileptic encephalopathy: exome screening and phenotype expansion. Epilepsia 2016; 57 (01) e12-e17
• 12 Pavone P, Praticò AD, Falsaperla R. et al. Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. Ital J Pediatr 2015; 41: 55
• 13 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) Ito Type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
• 14 Matricardi S, Spalice A, Salpietro V. et al. Epilepsy in the setting of full trisomy 18: a multicenter study on 18 affected children with and without structural brain abnormalities. Am J Med Genet C Semin Med Genet 2016; 172 (03) 288-295
• 15 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
• 16 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
• 17 Traynelis SF, Wollmuth LP, McBain CJ. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 2010; 62 (03) 405-496
• 18 Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994; 12 (03) 529-540
• 19 Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci 2011; 33 (08) 1351-1365
• 20 Wyllie DJA, Livesey MR, Hardingham GE. Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacology 2013; 74: 4-17
• 21 Watanabe M, Inoue Y, Sakimura K, Mishina M. Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport 1992; 3 (12) 1138-1140
• 22 Bar-Shira O, Maor R, Chechik G. Gene expression switching of receptor subunits in human brain development. PLOS Comput Biol 2015; 11 (12) e1004559
• 23 Henson MA, Roberts AC, Salimi K. et al. Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex. Cereb Cortex 2008; 18 (11) 2560-2573
• 24 Kumar SS, Huguenard JR. Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex. J Neurosci 2003; 23 (31) 10074-10083
• 25 Parsons MP, Raymond LA. Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 2014; 82 (02) 279-293
• 26 Strehlow V, Heyne H, Lemke J. The spectrum of GRIN2A-associated disorders. Epileptologie. 2015; 32: 147-151
• 27 Uhlhaas PJ, Singer W. Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale networks. Neuron 2012; 75 (06) 963-980
• 28 Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell 2014; 157 (01) 163-186
• 29 Sawtell NB, Frenkel MY, Philpot BD, Nakazawa K, Tonegawa S, Bear MF. NMDA receptor-dependent ocular dominance plasticity in adult visual cortex. Neuron 2003; 38 (06) 977-985
• 30 Rossi P, Sola E, Taglietti V. et al. NMDA receptor 2 (NR2) C-terminal control of NR open probability regulates synaptic transmission and plasticity at a cerebellar synapse. J Neurosci 2002; 22 (22) 9687-9697
• 31 Ruggieri M, McShane MA. Parental view of epilepsy in Angelman syndrome: a questionnaire study. Arch Dis Child 1998; 79 (05) 423-426
• 32 Lionetti E, Francavilla R, Maiuri L. et al. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr 2009; 49 (02) 202-207
• 33 Wu S-L, Wang W-F, Shyu H-Y. et al. Association analysis of GRIN1 and GRIN2B polymorphisms and Parkinson's disease in a hospital-based case-control study. Neurosci Lett 2010; 478 (02) 61-65
• 34 Lee J-Y, Lee EK, Park SS. et al. Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson's disease. Mov Disord 2009; 24 (12) 1803-1810
• 35 Zainal Abidin S, Tan EL, Chan S-C. et al. DRD and GRIN2B polymorphisms and their association with the development of impulse control behaviour among Malaysian Parkinson's disease patients. BMC Neurol 2015; 15: 59
• 36 Frizelle PA, Chen PE, Wyllie DJA. Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: Implications for studies of synaptic transmission. Mol Pharmacol 2006; 70 (03) 1022-1032
• 37 Cline H, Haas K. The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: a review of the synaptotrophic hypothesis. J Physiol 2008; 586 (06) 1509-1517
• 38 Gambrill AC, Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A 2011; 108 (14) 5855-5860
• 39 Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 2011; 71 (06) 1085-1101
• 40 O'Connor KC, Lopez-Amaya C, Gagne D. et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J Neuroimmunol 2010; 223 (1-2): 92-99
• 41 Ruggieri M, Huson SM. The neurofibromatoses. An overview. Ital J Neurol Sci 1999; 20 (02) 89-108
• 42 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
• 43 Ruggieri M, Praticò AD. Mosaic neurocutaneous disorders and their causes. Semin Pediatr Neurol 2015; 22 (04) 207-233
• 44 Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010; 11 (10) 682-696
• 45 Martel M-A, Ryan TJ, Bell KFS. et al. The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron 2012; 74 (03) 543-556
• 46 Ruggieri M, Tigano G, Mazzone D, Tiné A, Pavone L. Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromiens). Neurology 1996; 46 (02) 485-492
• 47 Pavone P, Praticò AD, Pavone V. et al. Ataxia in children: early recognition and clinical evaluation. Ital J Pediatr 2017; 43 (01) 6
• 48 Rajagopal S, Fitzgerald AA, Deep SN, Paul S, Poddar R. Role of GluN2A NMDA receptor in homocysteine-induced prostaglandin E2 release from neurons. J Neurochem 2019; 150 (01) 44-55
• 49 Kochetova OV, Avzaletdinova DS, Korytina GF, Morugova TV, Mustafina OE. The association between eating behavior and polymorphisms in GRIN2B, GRIK3, GRIA1 and GRIN1 genes in people with type 2 diabetes mellitus. Mol Biol Rep 2020; 47 (03) 2035-2046
• 50 Salpietro V, Polizzi A, Bertè LF. et al. Idiopathic intracranial hypertension: a unifying neuroendocrine hypothesis through the adrenal-brain axis. Neuroendocrinol Lett 2012; 33 (06) 569-573
• 51 Ruggieri M, Pavone P, Polizzi A. et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol 2004; 88 (11) 1429-1433
• 52 Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000; 159 (10) 745-749
• 53 Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C. Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015; 7 (07) 5532-5539
• 54 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
• 55 Moghaddam B, Krystal JH. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull 2012; 38 (05) 942-949
• 56 Belforte JE, Zsiros V, Sklar ER. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 2010; 13 (01) 76-83
• 57 Pavone P, Falsaperla R, Ruggieri M. et al. Clinical course of N-methyl-D-aspartate receptor encephalitis and the effectiveness of cyclophosphamide treatment. J Pediatr Neurol 2017; 15: 84-49
• 58 de Ligt J, Willemsen MH, van Bon BWM. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367 (20) 1921-1929
• 59 Dimassi S, Andrieux J, Labalme A. et al. Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability. Am J Med Genet A 2013; 161A (10) 2564-2569
• 60 Ruggieri M, Praticò AD, Evans DG. Diagnosis, management, and new therapeutic options in childhood neurofibromatosis type 2 and related forms. Semin Pediatr Neurol 2015; 22 (04) 240-258
• 61 Ruggieri M. Mosaic (segmental) neurofibromatosis type 1 (NF1) and type 2 (NF2): no longer neurofibromatosis type 5 (NF5). Am J Med Genet 2001; 101 (02) 178-180
• 62 Ruggieri M, Polizzi A, Spalice A. et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet 2015; 87 (05) 401-410
• 63 Grozeva D, Carss K, Spasic-Boskovic O. et al; Italian X-linked Mental Retardation Project, UK10K Consortium, GOLD Consortium. Targeted next-generation sequencing analysis of 1,000 individuals with intellectual disability. Hum Mutat 2015; 36 (12) 1197-1204
• 64 Zhang Y, Kong W, Gao Y. et al. Gene mutation analysis in 253 Chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One 2015; 10 (11) e0141782
• 65 Smigiel R, Kostrzewa G, Kosinska J. et al. Further evidence for GRIN2B mutation as the cause of severe epileptic encephalopathy. Am J Med Genet A 2016; 170 (12) 3265-3270
• 66 Tarabeux J, Kebir O, Gauthier J. et al; S2D team. Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry 2011; 1: e55
• 67 O'Roak BJ, Vives L, Fu W. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012; 338 (6114): 1619-1622
• 68 Freunscht I, Popp B, Blank R. et al. Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene. Behav Brain Funct 2013; 9: 20
• 69 DeVries SP, Patel AD. Two patients with a GRIN2A mutation and childhood-onset epilepsy. Pediatr Neurol 2013; 49 (06) 482-485
• 70 Myers SJ, Yuan H, Kang J-Q, Tan FCK, Traynelis SF, Low CM. Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000 Res 2019; 8: F1000 Faculty Rev-1940
• 71 Law AJ, Weickert CS, Webster MJ, Herman MM, Kleinman JE, Harrison PJ. Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. Eur J Neurosci 2003; 18 (05) 1197-1205
• 72 Jantzie LL, Talos DM, Jackson MC. et al. Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain. Cereb Cortex 2015; 25 (02) 482-495
• 73 Ruggieri M, Gabriele AL, Polizzi A. et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013; 14 (02) 89-98
• 74 Ruggieri M, Polizzi A. Segmental neurofibromatosis. J Neurosurg 2000; 93 (03) 530-532
• 75 Endele S, Rosenberger G, Geider K. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010; 42 (11) 1021-1026
• 76 Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957; 7 (08) 523-530
• 77 Kramer U, Nevo Y, Neufeld MY, Fatal A, Leitner Y, Harel S. Epidemiology of epilepsy in childhood: a cohort of 440 consecutive patients. Pediatr Neurol 1998; 18 (01) 46-50
• 78 Shinnar S, O'Dell C, Berg AT. Distribution of epilepsy syndromes in a cohort of children prospectively monitored from the time of their first unprovoked seizure. Epilepsia 1999; 40 (10) 1378-1383
• 79 Smith MC, Hoeppner TJ. Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep. J Clin Neurophysiol 2003; 20 (06) 462-472
• 80 Larsson K, Eeg-Olofsson O. A population based study of epilepsy in children from a Swedish county. Eur J Paediatr Neurol 2006; 10 (03) 107-113
• 81 Fejerman N, Caraballo R. Benign Focal Epilepsies in infancy, childhood and adolescence. 1st ed. Vol. 21.. Montrouge, France: John Libbey Eurotext; 2007
• 82 Loddenkemper T, Fernández IS, Peters JM. Continuous spike and waves during sleep and electrical status epilepticus in sleep. J Clin Neurophysiol 2011; 28 (02) 154-164
• 83 Tsai M-H, Vears DF, Turner SJ. et al. Clinical genetic study of the epilepsy-aphasia spectrum. Epilepsia 2013; 54 (02) 280-287
• 84 Dimassi S, Labalme A, Lesca G. et al. A subset of genomic alterations detected in Rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2. Epilepsia 2014; 55 (02) 370-378
• 85 Turner SJ, Morgan AT, Perez ER, Scheffer IE. New genes for focal epilepsies with speech and language disorders. Curr Neurol Neurosci Rep 2015; 15 (06) 35
• 86 Turner SJ, Mayes AK, Verhoeven A, Mandelstam SA, Morgan AT, Scheffer IE. GRIN2A: an aptly named gene for speech dysfunction. Neurology 2015; 84 (06) 586-593
• 87 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
• 88 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
• 89 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
• 90 Lemke JR, Lal D, Reinthaler EM. et al. Mutations in GRIN2A cause idiopathic focal epilepsy with Rolandic spikes. Nat Genet 2013; 45 (09) 1067-1072
• 91 Carvill GL, Regan BM, Yendle SC. et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013; 45 (09) 1073-1076
• 92 Venkateswaran S, Myers KA, Smith AC. et al; FORGE Canada Consortium. Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation. Epilepsia 2014; 55 (07) e75-e79
• 93 Reutlinger C, Helbig I, Gawelczyk B. et al. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the Rolandic region. Epilepsia 2010; 51 (09) 1870-1873
• 94 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
• 95 Lesca G, Rudolf G, Labalme A. et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia 2012; 53 (09) 1526-1538
• 96 Lesca G, Rudolf G, Bruneau N. et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013; 45 (09) 1061-1066
• 97 Yuan H, Hansen KB, Zhang J. et al. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun 2014; 5: 3251
• 98 Yuan Y, Yunhe M, Xiang W. et al. P450 enzyme-inducing and non-enzyme-inducing antiepileptic drugs for seizure prophylaxis after glioma resection surgery: a meta-analysis. Seizure 2014; 23 (08) 616-621
• 99 Lal D, Steinbrücker S, Schubert J. et al; Epicure consortium, EuroEPINOMICS-CoGIE consortium. Investigation of GRIN2A in common epilepsy phenotypes. Epilepsy Res 2015; 115: 95-99
• 100 Hughes JR. A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep. Epilepsy Behav 2011; 20 (02) 247-253
• 101 Dalla Bernardina B, Sgrò V, Fejerman N. Epilepsy with centro-temporal spikes and related syndromes. In: Roger J, Bur M, Dravet C, Genton P, Tassinari CA, Wolf P. eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed.. Montrouge, France: John Libbey Eurotext; 2005: 203-225
• 102 Morrell F, Whisler WW, Smith MC. et al. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain 1995; 118 (Pt 6): 1529-1546
• 103 Li X, Xie LL, Han W. et al. Clinical forms and GRIN2A genotype of severe end of epileptic-aphasia spectrum disorder. Front Pediatr 2020; 8: 574803
• 104 Pierson TM, Yuan H, Marsh ED. et al; PhD for the NISC Comparative Sequencing Program. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014; 1 (03) 190-198
• 105 Lesca G, Møller RS, Rudolf G, Hirsch E, Hjalgrim H, Szepetowski P. Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations. Epileptic Disord 2019; 21 (Suppl. 01) 41-47
• 106 Nicotera AG, Calì F, Vinci M, Musumeci SA. GRIN2A: involvement in movement disorders and intellectual disability without seizures. Neurol Sci 2019; 40 (11) 2405-2406
• 107 Li J, Zhang J, Tang W. et al. De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases. Hum Mutat 2019; 40 (12) 2393-2413
• 108 Addis L, Virdee JK, Vidler LR, Collier DA, Pal DK, Ursu D. Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue. Sci Rep 2017; 7 (01) 66
• 109 Farwell KD, Shahmirzadi L, El-Khechen D. et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015; 17 (07) 578-586
• 110 von Stülpnagel C, Ensslen M, Møller RS. et al. Epilepsy in patients with GRIN2A alterations: genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs. Eur J Paediatr Neurol 2017; 21 (03) 530-541
• 111 Serraz B, Grand T, Paoletti P. Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations. Neuropharmacology 2016; 109: 196-204
• 112 Hamdan FF, Srour M, Capo-Chichi J-M. et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet 2014; 10 (10) e1004772
• 113 Sceniak MP, Fedder KN, Wang Q. et al. An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth. J Cell Sci 2019; 132 (20) jcs232892
• 114 Kenny EM, Cormican P, Furlong S. et al. Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol Psychiatry 2014; 19 (08) 872-879
• 115 O'Roak BJ, Stessman HA, Boyle EA. et al. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat Commun 2014; 5: 5595
• 116 Mullier B, Wolff C, Sands ZA. et al. GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors. Neuropharmacology 2017; 123: 322-331
• 117 Bosch DG, Boonstra FN, de Leeuw N. et al. Novel genetic causes for cerebral visual impairment. Eur J Hum Genet 2016; 24 (05) 660-665
• 118 Caltabiano R, Magro G, Polizzi A. et al. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 2017; 33 (06) 933-940
• 119 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: first descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. Am J Med Genet A 2018; 176 (03) 515-550
• 120 Barbagallo M, Ruggieri M, Incorpora G. et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
• 121 Ruggieri M, Praticò AD, Serra A. et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
• 122 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
• 123 Platzer K, Yuan H, Schütz H. et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 2017; 54 (07) 460-470
• 124 Hu C, Chen W, Myers SJ, Yuan H, Traynelis SF. Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci 2016; 132 (02) 115-121
• 125 Platzer K, Lemke JR. GRIN2B-Related Neurodevelopmental Disorder. 2018. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020
• 126 Hildebrand MS, Myers CT, Carvill GL. et al. A targeted resequencing gene panel for focal epilepsy. Neurology 2016; 86 (17) 1605-1612
• 127 Yavarna T, Al-Dewik N, Al-Mureikhi M. et al. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum Genet 2015; 134 (09) 967-980
• 128 Retterer K, Juusola J, Cho MT. et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 2016; 18 (07) 696-704
• 129 Sharawat IK, Yadav J, Saini L. Novel GRIN2B mutation: a rare cause of severe epileptic encephalopathy. Neurol India 2019; 67 (02) 562-563
• 130 Stosser MB, Lindy AS, Butler E. et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet Med 2018; 20 (04) 403-410
• 131 Kyriakopoulos P, McNiven V, Carter MT, Humphreys P, Dyment D, Fantaneanu TA. Atypical Rett syndrome and intractable epilepsy with novel GRIN2B mutation. Child Neurol Open 2018; 5: X18787946
• 132 Murray E, McCabe P, Ballard KJ. A systematic review of treatment outcomes for children with childhood apraxia of speech. Am J Speech Lang Pathol 2014; 23 (03) 486-504
• 133 Van Bogaert P. Epileptic encephalopathy with continuous spike-waves during slow-wave sleep including Landau-Kleffner syndrome. Handb Clin Neurol 2013; 111: 635-640
• 134 Striano P, Capovilla G. Epileptic encephalopathy with continuous spikes and waves during sleep. Curr Neurol Neurosci Rep 2013; 13 (07) 360
• 135 Fainberg N, Harper A, Tchapyjnikov D, Mikati MA. Response to immunotherapy in a patient with Landau-Kleffner syndrome and GRIN2A mutation. Epileptic Disord 2016; 18 (01) 97-100
• 136 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
• 137 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
• 138 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
• 139 Falsaperla R, D'Angelo G, Praticò AD. et al. Ketogenic diet for infants with epilepsy: a literature review. Epilepsy Behav 2020; 112: 107361
• 140 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
• 141 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A [phone]
• 142 Soto D, Olivella M, Grau C. et al. L-serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy. Sci Signal 2019; 12 (586) eaaw0936