Neurological features
Epilepsy
Epilepsy is seen in 51% of affected individuals with an onset ranging from birth to 9 years and being refractory in half of cases. The spectrum of seizures covering epileptic spasms (35%), focal seizures (48%) and generalized seizures (58%) with numerous possible semiologies.
Developmental delay/Intellectual disability (DD/ID)
The degree of DD/ID can be severe or profound (73%), moderate (18%) or mild (10%) using standard assessments of psychomotor development or IQ testing.
Muscle Tone Abnormalities
Hypotonia has been reported in more than half of the individuals, spasticity in approximately one third.
ASD
Autistic features were seen in 16% of affected individuals.
EEG and neuroimaging findings
EEG recordings shows either focal, multifocal or generalized epileptiform activity and/or hypsarrhythmia.
Brain MRI is normal or shows brain abnormalities including malformation of cortical development (MCD) in 13%, cerebral atrophy, hypoplastic corpus callosum of varying degrees, enlarged and mildly dysplastic basal ganglia, hippocampal dysplasia with thick leaves and open hilus, absent septum pellucidum. The identified individuals with MCD display a very similar degree of severity, and there are no reports of affected individuals with less pronounced malformations of cortical development.
Clinical variability
The severity of GRIN2B-related neurodevelopmental disorder is variable. Most individuals will be severely impaired while other will have a milder phenotype. Penetrance of GRIN2B-related neurodevelopmental disorder is thought to be 100%.
Differential diagnosis
It can be difficult to differentiate individuals with GRIN2B-related neurodevelopmental disorder from similar disorders caused by pathogenic variants in neurodevelopmental disorder related genes. Genetic testing confirming the identification of a pathogenic variant in GRIN2B is therefore the only reliable test confirming the diagnosis. All genes known to be associated with ID, early-onset epileptic encephalopathy, and malformations of cortical development (especially diffuse polymicrogyria and tubulinopathies) should be included in the differential diagnosis of GRIN2B-related neurodevelopmental disorder.
GRIN2B