Response to immunotherapy in a patient with Landau‐Kleffner syndrome and <i>GRIN2A</i> mutation

Fainberg, Nina; Harper, Amy; Tchapyjnikov, Dmitry; Mikati, Mohamad A.

doi:10.1684/epd.2016.0791

Cited by 52 publications

(12 citation statements)

References 21 publications

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“…It has been showed that seizures can be induced by upregulating NMDA receptors on post-synaptic cells via an activation of the GluN2B subunit of the NMDA receptor [28].Once significant mutations occur to the RELN gene, the blocking of reelin protein will increase the concentration of GluN2B -NMDA [29], so as to trigger the seizure. Fainberg [30] once reported a patient with LKS and GRIN2A mutation, who was responsive to immunotherapy, suggesting that autoimmune mechanism could be a component of the underlying disease-causing factors. So this maybe another reason why our patient with RELN mutation was responsive to corticosteroids therapy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of methylprednisolone therapy in atypical Rolandic epilepsy with heterozygous RELN mutation

Hu¹,

Jing²,

Ying³

2019

Preprint

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Background: Atypical Rolandic epilepsy, also known as benign childhood epilepsy with centrotemporal spikes (BECTS) variant is defined by the appearance of severe neuropsychological impairments and refractory epilepsy. The etiology of the disease remains unclear, and recent studies indicated that it is related to several gene mutations. The suitable treatment is also need to be further explored. Here, we present the case of a 9-year-old boy with BECTS variant found to have heterozygous RELN mutation, responded well to the corticosteroid therapy. Case presentation: A 9-year-old male patient with atypical benign Rolandic epilepsy was successfully treated with high-dose intravenous methylprednisolone pulse therapy (15 mg/kg daily for 3 consecutive days, and the infusion was repeated three times with a 4-day interval between each course). The treatment improved his electroencephalogram (EEG) and cognitive performance, reduced seizure frequency, and the effect maintained for one year of follow-up. Whole-exome sequencing (WES) revealed a meaningful heterozygous missense mutation in the RELN gene. Conclusion: We conclude that corticosteroid therapy should be considered as a therapeutic option in patients with BECTS variant who are also found to harbour RELN mutations.

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Section: Discussionmentioning

confidence: 99%

Efficacy of methylprednisolone therapy in atypical Rolandic epilepsy with heterozygous RELN mutation

Hu¹,

Jing²,

Ying³

2019

Preprint

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“…Among the 14 cases which had clear intellectual evaluation in the literatures, 28.6% had normal IQ, 21.4% had mild ID/DD, 28.6% had moderate ID/DD, 14.3% had mild-moderate ID/DD, and only 7.1% had severe ID/DD. To the best of our knowledge, the treatment process of only two patients has been described in detail in all of the published literature in Table 6 (11,22). One of the two patients diagnosed with LKS were treated with prednisone and immunoglobin after being unresponsive to multiple AEDs, and the cognition of this patient improved gradually 6 months after prednisone and immunoglobin treatment.…”

Section: Literature Review Of Pathogenic Grin2a-lof Variantsmentioning

confidence: 98%

“…The mechanism could be as follows: (1) Autoimmune response was proved to contribute partially to the etiology of EAS. GRIN2A mutation itself could increase the antigenicity of extracellular components of NMDA receptor (22,24,39), and the seizure process might also increase the self-antigenicity of NMDA receptors (22). (2) Most likely, recent research presented that steroids can enhance the function of NMDA receptors and regulate glutamate activity.…”

Section: Treatmentmentioning

confidence: 99%

Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder

et al. 2020

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This study aims to analyze the electroclinical characteristics and gene test results of children on the severe end of the epilepsy aphasia spectrum (EAS) and also the correlation of EAS-related GRIN2A genes to explore the genotype-phenotype relationships, as well as potential pathogenic mechanism of EAS. Methods: A retrospective study was conducted on the participants diagnosed with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS), and atypical benign partial epilepsy (ABPE) at the Children's Hospital of Chongqing Medical University from January 2013 to June 2019. Whole-exome sequencing was performed in six patients, and epileptic panel was carried out in two. In addition, we reviewed all the published literatures reporting EAS patients with pathogenic variants until June 2019 and conducted Gene Ontology (GO) analysis, as well as protein-protein interaction (PPI) network. Results: The mean age at seizure onset was 55.4 ± 27.0 months. The baseline severity of the spike-wave index (SWI) was not significantly correlated with intellectual disability (ID) level. Two pathogenic de novo GRIN2A null variants were identified in patients with ABPE who had less severe ID, despite the electrical status epilepticus during slow-wave sleep (ESES). By literature reviewing, 18 GRIN2A missense mutations and 11 GRIN2A truncating mutations which lead to N-methyl-d-aspartate receptors' loss of function has been reported. Of these mutations, 9 (31.0%) are situated in amino (N)-terminal domain, 6 (20.7%) in linger-binding domain S1, and 10 (34.5%) in linger-binding domain S2. EAS-related genes were enriched in the biological process of chemical synaptic transmission and vocalization (FDR, <0.01). The hub protein in PPI network is GluN2A, which might affect language function via foxp2-srpx2/uPAR signal network. Conclusion: Our data suggested that when children suspected with benign epilepsy of children with centrotemporal spikes (BECTs) have early-onset age, changed seizure semiology, and deterioration of behavior/cognition/motor function, neurologists should be alert of the appearance of ESES. The neuropsychological deterioration in children Li et al. Epileptic-Aphasia Spectrum Disorder with EAS might not only be completely affected by electric discharge severity but also genetic etiology. Our finding also enforced the current genotype-phenotype relationship theory about EAS. For EAS children, GRIN2A-FOXP2-SRPX2/uPAR signal network might contribute to the mechanism of their language deficit.

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“…Intravenous immunoglobulin (IVIG) has been used for the therapy of Landau-Kleffner syndrome and other intractable epilepsy syndromes and epileptic encephalopathies, but the definitive placebo-controlled studies have not been performed, and thus, a recent Cochrane review concluded that definitive conclusions about its efficacy cannot be made at this stage [101][102][103]. A case report of Landau-Kleffner syndrome associated with a GRIN2A mutation described a patient whose syndrome responded only to steroid and IVIG therapy despite the presumed genetic etiology [104]. Therapy of autoimmune encephalitis currently consists of the following [105]: first-line immunotherapy includes intravenous steroids over 3-5 days (may need to be repeated if needed), IVIG (over 2 days then monthly), and plasmapheresis.…”

Section: Advances In the Therapy Of Epileptic Encephalopathies In Chimentioning

confidence: 99%

Novel therapies for epilepsy in the pipeline

Mesraoua

Deleu

Kullmann

et al. 2019

Epilepsy & Behavior

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Despite the availability of many antiepileptic drugs (AEDs) (old and newly developed) and, as recently suggested, their optimization in the treatment of patients with uncontrolled seizures, more than 30% of patients with epilepsy continue to experience seizures and have drug-resistant epilepsy; the management of these patients represents a real challenge for epileptologists and researchers. Resective surgery with the best rates of seizure control is not an option for all of them; therefore, research and discovery of new methods of treating resistant epilepsy are of extreme importance. In this article, we will discuss some innovative approaches, such as P-glycoprotein (P-gp) inhibitors, gene therapy, stem cell therapy, traditional and novel antiepileptic devices, precision medicine, as well as therapeutic advances in epileptic encephalopathy in children; these treatment modalities open up new horizons for the treatment of patients with drug-resistant epilepsy.

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Response to immunotherapy in a patient with Landau‐Kleffner syndrome and GRIN2A mutation

Cited by 52 publications

References 21 publications

Efficacy of methylprednisolone therapy in atypical Rolandic epilepsy with heterozygous RELN mutation

Efficacy of methylprednisolone therapy in atypical Rolandic epilepsy with heterozygous RELN mutation

Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder

Novel therapies for epilepsy in the pipeline

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