All About GRIN Disorder

GRIN Disorder is part of a larger family of genetic diseases related to ionotropic glutamate receptors and is caused by a change in one of seven GRIN genes including GRIN1, GRIN2A, GRIN2B, and GRIN2D. These genes contain the code to create NMDA receptors, which are essential for learning and memory.  NMDA receptors are made up of two GluN1 proteins (which are encoded by GRIN1) and two GluN2 proteins (which are encoded by GRIN2A, GRIN2B, or GRIN2D).  

Symptoms of GRIN Disorder include: developmental delay, intellectual disability, autism, speech deficiency, inability to walk, low muscle tone, gastrointestinal issues, feeding difficulties, cortical visual impairments, dystonia, seizures, and neuro storms.  

Most GRIN Disorder cases are caused by de novo missense variants. It has been predicted that GRIN Disorders due to variants in either GRIN1, GRIN2A, GRIN2B or GRIN2D occur in one out of every 5,208 births (19.2 per 100,000) (Lemke, 2020).  

For GRIN1, the predicted incidence per 100,000 births is 5.45. There were 3,791,712 babies born in the U.S. in 2018, and using the prediction model, this would mean that 207 babies born would be predicted to be affected with a variant in GRIN1 in the U.S. in 2018 (Lemke, 2020).  

For GRIN2A, the predicted incidence per 100,000 births is 3.23. Using the prediction model, the predicted number of affected babies with a variant in GRIN2A born in the U.S. in 2018 is 122. GRIN2A-related Disorder is likely significantly underestimated because these numbers do not capture individuals without intellectual disability, who are estimated to make up more than a third of the GRIN2A patient population (Lemke, 2020).  

For GRIN2B, the predicted incidence per 100,000 births is 5.91. By using the prediction model, the number of affected babies predicted to have a variant in GRIN2B born in the U.S. in 2018 is 224. GRIN2B-related Disorder appears to have the highest incidence among all GRIN-related disorders (Lemke, 2020).  

For GRIN2D, the predicted incidence per 100,000 births is 4.61. Using the prediction model, the predicted number of affected babies with a variant in GRIN2D born in the U.S. in 2018 is 175. This finding appears to overestimate the prevalence of GRIN2D cases. We know of fewer than 20 individuals living with disease-causing GRIN2D variants (Lemke, 2020).  

Several research studies have been conducted to find possible treatments targeting the NMDA receptors in GRIN disorders. However, there have been no FDA-approved treatments of GRIN disorders yet. Memantine is a NMDAR antagonist that has been tried in patients with GRIN1, GRIN2A, and GRIN2B gain-of-function variants and has been shown to reduce the frequency of seizures in some patients. L-Serine is a NMDAR agonist that has been shown to improve motor impairments, cognition, and communication in a patient with a GRIN2B loss-of-function variant. There is currently an ongoing clinical trial to test the tolerability and efficacy of L-Serine in more patients with GRIN Disorder. Additionally, Radiprodil is a negative allosteric modulator (NAM) of NMDARs, and there is an upcoming clinical trial to test Radiprodil in patients with GRIN2B gain-of-function variants.