Introduction To GRIN Disorders

What are GRIN disorders?

GRIN stands for Glutamate Receptor, Ionotropic, N-Methyl D-Aspartate. GRIN genes therefore encode the proteins that form the ionotopic glutamatergic NMDA (N-Methyl D-Aspartate) neuroreceptor.  

The GRIN genes are in charge of making important proteins called GluN, so for example: the GRIN1 gene makes GluN1, GRIN2A makes GluN2A, and so on… These GRIN proteins pair up in groups of 4 (tetramers) and form channel like structures in the cell wall of the neurons. The channel the GRIN proteins form is called the NMDA receptor. These channels help the neurons communicate with each other.  

Our brains learn and collect memories through complicated connections between neurons (specialized cells in your brain, which however can also be found in other parts of our body). Neurons connect with each other via electrical impulses that are generated when small molecules are expelled from one neuron and reach another, these small molecules are called neurotransmitters. 

These neurotransmitters, once released by one neuron, interact with neuroreceptors on a neighboring neuron. There are different types of neuroreceptors, but when we talk about GRIN, we think about ionotropic glutamatergic neurorecptors.  These neuroreceptors form channels that connect the outside of the neurons to the inside of these cells. So, when a neurotransmitter attaches to a neuroreceptor, it acts like a key in a lock, the neurotransmitter opens the neuroreceptor channel allowing the neuron to get activated. This happens because with an open channel, the neuron allows ions from the outside space to get inside the neuron. This in turn activates the receiving neuron and causes it to “fire” and release more neurotransmitters which will reach other surrounding neurons, creating a cascade of neurons connected by the same stimulus.  These events are key for learning and essential for memory formation, and it is here where our GRIN kids differ from most people.

In GRIN disorders, the communication between neurons is altered because the GRIN genes that have the instructions on how to build an NMDA receptor, are faulty. Since the NMDA receptor is made up of 4 different GluN proteins, it only takes one wrong GRIN protein to get a faulty neuroreceptor.  If the NMDA receptor does not function well then, the neurons do not get the right signal. Basically, this is how GRIN genes (and mutations in these genes) have a direct effect on learning and memory. 

Until now neurodevelopmental disorders have been associated with mutations in 4 different GRIN genes known. These are GRIN1, GRIN2A, GRIN2B and GRIN2D. So far, no neurodevelopmental disorders have been associated with the GRIN2C, GRIN3A and GRIN3B genes. NMDA receptors are found primarily in the brain, but they can also be found in other organs such as the heart, the gut, and on the muscle cells in our body.  Consequently, our GRIN children often also struggle with gastro intestinal issues and with their gross and fine motor skills and suffer from either hypotonia (low muscle tone), hypertonia (high muscle tone) or dystonia (a mix or the former two). 

The abnormal function of the NMDA receptors has also been associated with common diseases such as Alzheimer’s Disease, depression, schizophrenia and autism spectrum disorder (ASD). The great interest in finding treatments and cures for Alzheimer´s Disease and Autism will hopefully also lead to the accelerated development of treatments for GRIN-related disorders.

GRIN disorders were first described in 2011 and they are considered part of the neuro-metabolic and epileptic rare disease group of disorders. Because GRIN disorders were discovered so recently, the number of specialists (physicians and researchers) working with children with GRIN disorders or studying GRIN disorders is unfortunately still very limited.  This makes it so hard for families to get appropriate advice on the treatment for this group of pathologies. Parents of GRIN patients are therefore often left alone in the search for answers and treatment options for their children. Support by the different patient associations and family groups is thus critical and can also help to inform doctors and healthcare providers about the disease spectrum.

Through our association we are working closely with many parent groups (see GRIN GROUPS section) and referral hospitals to try to help increase and spread knowledge about GRIN related diseases across Europe and beyond. 

For more information see: 

Explanation of the NMDA by Elliot Nicholson