Preliminary Study About A Significant and Treatable Cause of Epileptic Encephalopathy: GRIN2D Mutation

Year 2021, , 109 - 117, 30.08.2021

Gültekin Kutluk , Nadide Cemre Randa

https://doi.org/10.30565/medalanya.891938

Cited By: 1

Abstract

Aim: The GRIN2D gene mutation causes severe forms of epileptic encephalopathy. NMDAR antagonists and magnesium sulfate could be useful as adjunctive therapy to control seizures in individuals with GRIN2D encephalopathy. The aim of this study was to describe the clinical features and treatment options of GRIN2D encephalopathy.

Methods: Patients followed up with epileptic encephalopathy in our pediatric neurology clinic were investigated for genetic etiology using next-generation sequencing (NGS)-based tests. Patients with the GRIN2D mutation were overviewed for clinical and genetic characteristics.

Results: A total of 53 patients were screened and GRIN2D mutations (c.3684_3685insGA, c.3248_3254del, c.1579G>T, c.47_49del) were detected in four patients. Occipital epileptic activity was frequently detected among our patients. Three patients received memantine treatment for intractable epilepsy and remained seizure-free.

Conclusion: GRIN2D encephalopathy is a treatable epileptic encephalopathy, and its recognition is important in terms of outcomes. Occipital epilepsy is generally benign, but developmental and epileptic encephalopathies such as GRIN2D encephalopathy should be considered in the presence of concomitant developmental delay.

Keywords

developmental delay, epileptic encephalopathy, GRIN2D, memantine, NMDA

Epileptik Ensefalopatinin Önemli ve Tedavi Edilebilir Bir Nedeni Hakkında Ön Çalışma: GRIN2D Mutasyonu

Abstract

Amaç: GRIN2D gen mutasyonu, ağır epileptik ensefalopatiye neden olur. NMDAR antagonistleri ve magnezyum, GRIN2D ensefalopatili bireylerde nöbetleri kontrol etmek için faydalı bir tedavi seçeneği olabilir. Bu çalışmanın amacı GRIN2D ensefalopatisinin klinik özellikleri ile tedavi seçeneklerini tanımlamaktır.

Yöntemler: Çocuk nöroloji kliniğimizde epileptik ensefalopati ile izlenen hastalar genetik etiyoloji açısından yeni nesil dizileme yöntemi tabanlı testler ile incelendi. GRIN2D mutasyonu olan hastalar klinik ve genetik özellikler açısından değerlendirildi.

Bulgular: Toplam 53 hasta tarandı. 4 hastada GRIN2D mutasyonları (c.3684_3685insGA, c.3248_3254del, c.1579G>T, c.47_49del) tespit edildi. Hastalarımızda oksipital epileptik aktivite sıklıkla tespit edildi. 3 hastaya inatçı epilepsi için memantin tedavisi başlandı ve bu hastalar nöbetsiz olarak takip edilmekteler.

Sonuç: GRIN2D ensefalopati, tedavi edilebilir bir epileptik ensefalopatidir ve hastanın sağkalımı açısından tanınması önemlidir. Oksipital epilepsi genellikle iyi huyludur, ancak eşlik eden gelişimsel gecikme varlığında GRIN2D ensefalopatisi gibi gelişimsel ve epileptik ensefalopatiler akla gelmelidir.

Keywords

gelişme geriliği, GRIN2D, NMDA, epileptik ensefalopati, memantin

References

• 1. Tarabeux J, Kebir O, Gauthier J, Hamdan FF, Xiong L, Piton A, et al. Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Translational Psychiatry 2011;1. https://doi.org/10.1038/tp.2011.52.
• 2. Perszyk RE, DiRaddo JO, Strong KL, Low CM, Ogden KK, Khatri A, et al. GluN2D-containing N-methyl-D-aspartate receptors mediate synaptic transmission in hippocampal interneurons and regulate interneuron activity. Molecular Pharmacology 2016;90:689–702. https://doi.org/10.1124/mol.116.105130.
• 3. Camp CR, Yuan H. GRIN2D/GluN2D NMDA receptor: Unique features and its contribution to pediatric developmental and epileptic encephalopathy. European Journal of Paediatric Neurology 2020;24:89–99. https://doi.org/10.1016/j.ejpn.2019.12.007.
• 4. Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, et al. GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. American Journal of Human Genetics 2016;99:802–16. https://doi.org/10.1016/j.ajhg.2016.07.013.
• 5. Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Annals of Clinical and Translational Neurology 2014;1:190–8. https://doi.org/10.1002/acn3.39.
• 6. Marimuthu P, Varadarajan S, Krishnan M, Shanmugam S, Kunjuraman GR, Ravinder J, et al. Evaluating the efficacy of memantine on improving cognitive functions in epileptic patients receiving anti-epileptic drugs: A double-blind placebo-controlled clinical trial (Phase IIIb pilot study). Annals of Indian Academy of Neurology 2016;19:344–50. https://doi.org/10.4103/0972-2327.179971.
• 7. McMullin D. Epi4K: Gene discovery in 4,000 genomes. Epilepsia 2012;53:1457–67. https://doi.org/10.1111/j.1528-1167.2012.03511.x.
• 8. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.
• 9. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676–85. https://doi.org/10.1111/j.1528-1167.2010.02522.x.
• 10. McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. The Lancet Neurology 2016;15:304–16. https://doi.org/10.1016/S1474-4422(15)00250-1.
• 11. Lemke JR, Hendrickx R, Geider K, Laube B, Schwake M, Harvey RJ, et al. GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy. Annals of Neurology 2014;75:147–54. https://doi.org/10.1002/ana.24073.
• 12. Ware TL, Huskins SR, Grinton BE, Liu YC, Bennett MF, Harvey M, et al. Epidemiology and etiology of infantile developmental and epileptic encephalopathies in Tasmania. Epilepsia Open 2019;4:504–10. https://doi.org/10.1002/epi4.12350.
• 13. Jain P, Sharma S, Tripathi M. Diagnosis and Management of Epileptic Encephalopathies in Children. Epilepsy Research and Treatment 2013;2013:1–9. https://doi.org/10.1155/2013/501981.
• 14. von Deimling M, Helbig I, Marsh ED. Epileptic Encephalopathies—Clinical Syndromes and Pathophysiological Concepts. Current Neurology and Neuroscience Reports 2017;17. https://doi.org/10.1007/s11910-017-0720-7.
• 15. XiangWei W, Kannan V, Xu Y, Kosobucki GJ, Schulien AJ, Kusumoto H, et al. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy. Brain 2019;142:3009–27. https://doi.org/10.1093/brain/awz232.
• 16. Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 2015;56:707–16. https://doi.org/10.1111/epi.12954.
• 17. Zhou L, Deng J, Stenton SL, Zhou J, Li H, Chen C, et al. Case Report: Rapid Treatment of Uridine-Responsive Epileptic Encephalopathy Caused by CAD Deficiency. Frontiers in Pharmacology 2020;11. https://doi.org/10.3389/fphar.2020.608737.
• 18. Assi L, Saklawi Y, Karam PE, Obeid M. Treatable Genetic Metabolic Epilepsies. Current Treatment Options in Neurology 2017;19. https://doi.org/10.1007/s11940-017-0467-0.
• 19. Tampi R, van Dyck C. Neuropsychiatric Disease and Treatment 2007:3(2) Memantine: efficacy and safety in mild-to-severe Alzheimer’s disease. doi:10.2147/nedt.2007.3.2.245.
• 20. Aman MG, Findling RL, Hardan AY, Hendren RL, Melmed RD, Kehinde-Nelson O, et al. Safety and efficacy of memantine in children with autism: Randomized, placebo-controlled study and open-label extension. Journal of Child and Adolescent Psychopharmacology 2017;27:403–12. https://doi.org/10.1089/cap.2015.0146.