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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 2  |  Page : 562-563

Novel GRIN2B mutation: A rare cause of severe epileptic encephalopathy

Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication13-May-2019

Correspondence Address:
Dr. Lokesh Saini
Pediatric Neurology and Neurodevelopment Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.257986

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How to cite this article:
Sharawat IK, Yadav J, Saini L. Novel GRIN2B mutation: A rare cause of severe epileptic encephalopathy. Neurol India 2019;67:562-3

How to cite this URL:
Sharawat IK, Yadav J, Saini L. Novel GRIN2B mutation: A rare cause of severe epileptic encephalopathy. Neurol India [serial online] 2019 [cited 2022 Jul 1];67:562-3. Available from: https://www.neurologyindia.com/text.asp?2019/67/2/562/257986


A 4-year old girl presented with delayed developmental milestones since 1 year of age. She was born to nonconsanguineous parents with an unremarkable perinatal period. She attained age-appropriate developmental milestones till 1 year of age. Then, she had frequent (five to six episodes/day) head drops. This was followed by stagnation of milestones. The child also developed poor eye contact, repetitive hand movements, and frequent episodes of characteristic sobbing and sagging breathing pattern. She could walk with support, had a stranger anxiety, did not follow one step commands, and did not produce any meaningful words. The family history was non-contributory. On examination, she had hand stereotypes, frequent episodes of hypo- and hyperpnoea, a poor eye contact, microcephaly (44 cm), and central hypotonia. The possibilities of Rett's syndrome and epileptic encephalopathy were considered.

Investigations revealed a normal cerebrospinal fluid sugar (56 mg/dL), a normal magnetic resonance imaging (MRI) of the brain [Figure 1], and a normal magnetic resonance spectroscopy (MRS). Electroencephalogram showed abundant generalized bursts of spike/bi-spike and polyspike slow waves of 1–3 Hz and 200–400 μV [Figure 2]. Next-generation sequencing revealed a missense variation in exon 3 of GRIN2B gene (chr12: c.623C>T [p. Ser208Phe]). The Ser208Phe variant has not been reported yet and its pathogenicity was confirmed by in silico predictions. Based on the clinical features and next-generation sequencing, a diagnosis of GRIN2B-related early infantile epileptic encephalopathy was concluded. She was started on sodium valproate (20 mg/kg/day) and clonazepam (0.05 mg/kg/day) along with stimulation therapy. As electroencephalogram (EEG) revealed marked abnormalities, a course of oral steroids (prednisolone at 2 mg/kg/day for 4 weeks, followed by tapering) was also prescribed. The child responded to the therapy with marked improvement in behavioral symptoms and remained seizure-free for the next 4 months of follow-up.
Figure 1: Magnetic resonance imaging of the brain. T2-weighted axial (a) and coronal sections (b) showed normal intracranial structures

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Figure 2: Electroencephalogram. A sedated electroencephalogram (international 10-20 system, average montage, sensitivity 20μV/mm, sweep speed 30mm/s) showing abundant generalized bursts of spike/bi-spike and polyspike slow waves of 1–3 Hz and 200–400 μV

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GRIN2B is one of the four genes that encode N-methyl-D-aspartate receptor (NMDAR) subunits.[1] NMDARs are ligand-gated ion channels which mediate excitatory neurotransmission and play an important role in various cognitive functions such as learning and memory.[2] Patients with de novo pathogenic mutations in the GRIN2B gene usually present with various neurodevelopmental disorders which include epilepsy, including epileptic encephalopathy, autistic spectrum disorders, developmental delay, and intellectual disability.[3] Rarely, these patients may have predominant movement disorders such as dystonia and choreoathetoid movements.[4] Seizures may be present from birth to 9 years of age and include generalized, focal seizures and epileptic spasms. Magnetic resonance imaging (MRI) of the brain reveals abnormal findings in approximately10%–20% patients and include polymicrogyria, thinning of the corpus callosum, dysplastic basal ganglia, hippocampal dysplasia, and diffuse cortical atrophy.[1],[5] This particular entity needs a clear and early distinction from conditions such as Rett's syndrome as it may have significant genetic implications. In conclusion, patients with unexplained developmental delay, autistic features, and epileptic encephalopathy should be screened for GRIN2 gene-related mutations. We also suggest a possible role of immunotherapy in this group of disorders based on the response seen in the index child and with a clinical plausibility of immunotherapy working in these conditions owing to the involvement of NMDAR in the pathophysiology of this condition.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Platzer K, Yuan H, Schütz H, Winschel A, Chen W, Hu C, et al. GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 2017;54:460-70.  Back to cited text no. 1
Burnashev N, Szepetowski P. NMDA receptor subunit mutations in neurodevelopmental disorders. Curr Opin Pharmacol 2015;20:73-82.  Back to cited text no. 2
Takasaki Y, Koide T, Wang C, Kimura H, Xing J, Kushima I, et al. Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Sci Rep 2016; 6(1). Available from: http://www.nature.com/articles/srep3331. [Last cited on 2017 Dec 04]  Back to cited text no. 3
Hu C, Chen W, Myers SJ, Yuan H, Traynelis SF. Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci 2016;132:115-21.  Back to cited text no. 4
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: GRIN2B mutations in epilepsy. Ann Neurol 2014;75:147-54.  Back to cited text no. 5


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