Authors :
Presenting Author: Sergiusz Jóźwiak, MD, PhD – The Children's Memorial Health Institute
Aleksandra Nogowska-Glabien, MD – The Children's Memorial Health Institute
Mikolaj Pielas, MD – The Children's Memorial Health Institute
Kinga Szczepaniak, MD – The Children's Memorial Health Institute
Katarzyna Kotulska, MD, PhD – The Children's Memorial Health Institute
Rationale:
GRIN disorders are a newly discovered group of genetic neurodevelopmental disorders resulting from mutations in genes GRIN1, GRIN2A, GRIN2B and GRIN2D, that code for subunits of the N-methyl-D-aspartate (NMDA) receptor, leading to impaired glutamate signaling. Little is known about the GRIN-related epilepsies beginning in newborns and young infants.
Methods:
This retrospective study reviewed the medical records of pediatric patients with infantile epilepsy and confirmed GRINspectrum mutations treated at the Children’s Memorial Health Institute between 2017 and 2025. Data collected included genetic findings, seizure types, comorbidities, and treatment approaches.
Results:
We identified three patients with GRIN gene–related epilepsy. Information on the genetic mutations in individual patients is provided in Table 1:
| |
Gene
|
Nucleotide Change
|
Protein Change
|
Functional Effect
|
|
Patient 1
|
GRIN2A
|
c.1903G >A
|
p.Ala635Thr
|
Gain of function
|
|
Patient 2
|
GRIN2B
|
c.1849T >A
|
p.Ser617Thr
|
Pending
|
|
Patient 3
|
GRIN2B
|
c.2320C >T
|
p.Arg774Cys
|
Pending
|
Detailed characteristics of the individual patients are as follows:
Patient 1: Seizure onset occurred within the first month of life. The patient experienced daily seizures: tonic, focal clonic and epileptic spasms. He developed intellectual disability and spastic quadriplegia. Brain MRI was normal. EEG findings showed generalized slowing, absence of sleep features, and focal and generalized interictal epileptiform discharges. At the age of 9 years and despite polytherapy epilepsy is uncontrolled.
Patient 2: Seizures began in the second month of life. The patient developed drug-resistant epilepsy with daily seizures. Several types of seizures were present: tonic-clonic, clonic, and epileptic spasms. Patient developed severe intellectual disability and spastic quadriplegia. Brain MRI revealed diffuse cortico-subcortical atrophy. EEG demonstrated focal interictal epileptiform discharges with secondary generalization and generalized slowing. Currently, the patient is 6-year-old and experiences daily seizures.
Patient 3:
Seizures began in the first month of life. They appeared daily and quickly became pharmacoresistant epilepsy. Several types of seizures have been registered: focal seizures with impaired awareness, non-motor seizures and tonic seizures with autonomic features. The patient developed moderate developmental delay but retained normal motor function. Brain MRI was normal. EEG showed both focal and generalized interictal epileptiform discharges.
Now, the patient is 6 years old. Despite polyteherapy including antiseizure medications and neuroleptics, the patients presents with daily seziures and behavioral abnormalities.
Conclusions: This case series of patients with mutations in GRIN2A and GRIN2B highlights the possible early-onset, drug-resistant nature of GRIN-related epilepsies frequently associated with developmental delay. These findings underscore the clinical relevance of GRIN mutations in infantile developmental and epileptic encephalopathies and the need for new targeted treatment strategies.
Funding:
The study has been partly supported by project TAP-GRIN within Joint Transnational Call for Proposals EP PerMed JTC2024-329.