ABSTRACT

INTRODUCTION. Encephalopathy associated with a mutation in the GRIN genes is a brain disease caused by a malfunction of the N-methyl-D-aspart receptor. NMDA receptors (NMDA) are cation-specific ligand-dependent ion channels that provide glutamatergic synaptic transmission in the central nervous system. NMDAR has the structure of a heterotetrameric complex containing glutamate-binding and glycine-binding subunits encoded by genes of the GRIN family (GRIN1 – GRIN3). As a result of mutations, the subunit composition of the receptor changes, and with it the effects of its activation.

AIM. To analyze domestic and foreign publications on encephalopathies associated with mutations in the GRIN genes and their targeted therapy. To present a clinical case of a patient with GRIN2A-encephalopathy.

MATERIALS AND METHODS. The analysis of domestic and foreign publications for the period 2006-2024 is carried out. The sources of the RSCI, PubMed databases were used, ClinicalTrials.gov, Embase, SCOPUS. A clinical case is presented.

RESULTS AND DISCUSSION. In the case of the pathogenic variant of GRIN2A, which causes an increase in NMDAR function, the rational use of non-competitive receptor antagonists, such as memantine. In turn, when function is impaired, one of the best options is the use of co-agonists, for example, L-serine. The results of recent studies on the effective use of L-serine in children with genetically confirmed encephalopathy caused by a defect in the GRIN gene are presented. The results of L-serine therapy were a decrease in the frequency and intensity of epileptic seizures, an improvement in the electroencephalogram (EEG) picture, positive dynamics of adaptive behavior, cognitive and emotional spheres, motor functions, and the average quality of life of children.

CASE PRESENTATION. A case of a very rare epileptic syndrome is presented - developmental encephalopathy and epileptic encephalopathy with spike-wave activation during sleep associated with a heterozygous mutation in exon 11 of the GRIN2A gene (chr16:9892212C>T), leading to an amino acid substitution at position 760 of the protein (p.Gly760Ser, NM_001134407.2). The clinical picture includes pharmacoresistant epileptic seizures, prolonged spike-wave activity during sleep, behavioral disorders, and rapid and severe neurocognitive regression. Complete seizure relief and significant and lasting improvement in cognitive function and behavior were achieved as a result of low-dose hormone therapy with dexamethasone and high-dose L-serine therapy.

CONCLUSION. The presented clinical case is an example of the rapid transformation of self-limited epilepsy with central-temporal spikes, with an atypical course, into developmental epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), some cases of which have a genetic basis and may be the result of monogenic or complex inheritance. The main monogenic cause is the GRIN2A mutation. Pathogenic variants of GRIN2A are associated with a wide range of phenotypes of varying severity. In cases of severe and pharmacoresistant course, early inclusion in L-serine therapy at doses of at least 500 mg/kg/day is advisable.

KEYWORDS: GRIN2A-encephalopathy, GRIN gene, L-serine, developmental encephalopathy, epileptic encephalopathy

For citation: Korotkikh M.Yu., Skrynnik A.R., Korotkikh G.A. Efficacy of L-serine in Targeted Therapy of GRIN2A-developmental and Epileptic Encephalopathy: Case Report. Comorbidity Neurology. 2025; 2 (1): 83-89. https://doi.org/10.62505/3034-185x-2025-2-1-83-89

*For correspondence: Mikhail Y. Korotkikh, Cand. Sci. (Med.), Associate Professor of the Department of Psychiatry and Neurology, Medical Institute, Orel State University, Orel, Russia. E-mail: m.korotkich@gmail.com

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ADDITIONAL INFORMATION

Mikhail Y. Korotkikh, Cand. Sci. (Med.), Associate Professor of the Department of Psychiatry and Neurology, Medical Institute, Orel State University, Orel, Russia. E-mail: m.korotkich@gmail.com. ORCID: https://orcid.org/0000-0002-8294-5280

Anastasia R. Skrynnik, student, Medical Institute, Orel State University, Orel, Russia. E-mail: nastyacezаr@yandex.ru. ORCID: https://orcid.org/0009-0006-0222-8852

Galina A. Korotkikh, functional diagnostics physician,  University Polyclinic, Orel State University, Orel, Russia. E-mail: g.korotkich@gmail.com. ORCID: https://orcid.org/0009-0007-3365-5408

Author contributions. All authors confirm that their authorship complies with the international ICMJE criteria (all authors made a significant contribution to the development of the concept, the conduct of the study and the preparation of the article, read and approved the final version before publication). Special contributions: Korotkikh M.Yu. – conceptualization, methodology, formal analysis, investigation, data curation, writing – review & editing; Skrynnik A.R. – Validation, formal analysis; Korotkikh G.A. – conducting EEG-videomonitoring.

Funding. This study was not supported by any external sources of funding.

Disclosure. The authors declare no apparent or potential conflicts of interest related to the publication of this article.

Informed consent for publication. All patients, and if it is impossible to review and sign, persons responsible for the patients (relatives, social workers, etc.) on behalf of the patients undergoing examination and participating in this study, signed informed consent.

The content is available under the Creative Commons Attribution 4.0 License.

©2025. Mikhail Yu. Korotkikh, Anastasia R. Skrynnik, Galina A. Korotkikh