Neurological features
Epilepsy/EEG
Epilepsy is seen in 88% with an onset ranging from birth to 8 years. Many individuals have seizure offset around adolescence (between 8 and 20 years). Focal epilepsy was present in 57% of cases, 40% of which had a centrotemporal focus and similarities to the spectrum of Rolandic epilepsy. About 34% of cases had an EEG pattern of continuous spikes and waves during slow wave sleep.
Developmental delay/Intellectual disability (DD/ID)
Whereas 37% of affected individuals have normal intellect, 63% have ID that is usually mild (46%), but can also be moderate (22%), severe (11%) or profound (21%).
Muscle Tone Abnormalities
Hypotonia has been reported in one third of the individuals
ASD/psychiatric problems
Autistic features were seen in 10% of affected individuals, schizophrenia in 3%.
Language/Speech abnormalities
A seemingly unique feature among GRIN-related disorders is the spectrum of language and speech abnormalities found in GRIN2A-related neurodevelopmental disorder, including dysarthria, speech dyspraxia, dysphasia, speech regression with residual impairments found in 39% of cases. An additional 19% had aphasia.
Neuroimaging findings
Brain imaging is usually normal and only a minority of 14% reveals unspecific changes.
Clinical variability
The severity of GRIN2A-related neurodevelopmental disorder is variable. Penetrance of GRIN2A-related neurodevelopmental disorder is incomplete but high.
Differential diagnosis
It can be difficult to differentiate individuals with GRIN2A-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 GRIN2A is therefore the only reliable test confirming the diagnosis. All genes known to be associated with DD/ID, epilepsy, and speech abnormalities should be included in the differential diagnosis of GRIN2A-related neurodevelopmental disorder.
GRIN2A