Clinical Characteristics

Neurological features
Epilepsy is seen in 65% of affected individuals with an onset ranging from birth to 11 years and being refractory in nearly two third of cases. The spectrum of seizures covering epileptic spasms (13%), focal seizures (20%) and generalized seizures (68%) with numerous possible semiologies.

Developmental delay/Intellectual disability (DD/ID)
The degree of DD/ID can be severe or profound (88%), moderate (7%) or mild (5%) 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 40%.

Autistic features were seen in 22% 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 10%, leukoencephalopathy or cerebral atrophy. The MCD was similar in appearance to tubulinopathy-related or GRIN2B-related dysgyria.

Clinical variability
The severity of GRIN1-related neurodevelopmental disorder is variable. Most individuals will be severely impaired while other will have a milder phenotype. Penetrance of GRIN1-related neurodevelopmental disorder is thought to be 100%.

Differential diagnosis
It can be difficult to differentiate individuals with GRIN1-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 GRIN1 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 GRIN1-related neurodevelopmental disorder.