Individuals with GRIN2D-related neurodevelopmental disorder are regularly seen by a neurologist to monitor antiepileptic drug levels, to perform EEG recordings, motor and cognitive development. Motor and cognitive development is assessed with neuropsychological evaluations when appropriate. Surveillance of ocular and gastrointestinal function is also recommended.  

Treatment of manifestations
Anti-epileptic drugs are used to minimize seizure frequency. Rehabilitation of motor and cognitive functions is recommended. Physical therapy is recommended to maximize mobility as well as the use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., medication used to treat attention-deficit/hyperactivity disorder) when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Precision medicine approaches
Several pathogenic variants in numerous GRIN genes have been confirmed to result in either gain or loss of function of the NMDA receptor, which enables to potentially approach this dysfunction with either NMDA-specific blockers or enhancers. A first proof of principle has been established by treating an individual with epileptic encephalopathy due to a pathogenic de novo gain-of-function variant in GRIN2A with the NMDA receptor blocker memantine leading to a marked drop in seizure frequency. Many individuals with GRIN-related disorders have been treated with memantine since that and several of them have been published. Regarding GRIN2D, two individuals have been published to experience mild to moderate improvement in seizure burden and development after memantine application. The older individual subsequently developed refractory status epilepticus, with dramatic electroclinical improvement upon treatment with ketamine and magnesium.

With respect to loss-of-function variants, one individual with a pathogenic variant in GRIN2B has been reported to experience improvements in behavior, sleep and motor development after application of L-serine. In summary, precision medicine approaches in GRIN-related disorders appear to be potentially possible, but currently remain to be proven within double-blinded placebo-controlled clinical trials targeting objective parameters.