Introduction to GRIA disorder
Home /The GRIA genes encode AMPA receptors (AMPARs) which produce very short and fast electrical currents – so short they can transmit over 100 separate currents every second. They play a crucial role in conveying most electrical signals between brain cells. Disruption of their normal behavior due to genetic variants can have serious consequences for brain function and development. Changes that cause receptors to carry too much current (gain-of-function, GoF), or too little current (loss-of-function, LoF) have been identified in GRIA disorder patients.
Similar to GRIN disorder, GRIA disorder manifests with diverse symptoms ranging from mild intellectual disability or autism to severe neurodevelopmental disorders with untreatable epilepsy. These different outcomes are because each variant can occur at any part of these large proteins meaning each variant can potentially result in different changes from the way healthy receptors behave. The chances of the same spontaneous variant appearing in more than one patient is very small, and less than 20% of GRIA disorder patients have received the combination of specialist clinical assessment and scientific investigation of their variant that has been necessary to make such strong progress with GRIN disorder, hindering a comprehensive understanding of the disease.
We do however have a general overview of symptoms. All GRIA gene variants result in varying degrees of intellectual disability, and around half of the patients experience some form of epilepsy. Additional common symptoms include abnormal muscle tone (hypertonia or hypotonia), sleep disturbance, communication deficits, and behavioral difficulties.
AMPAR ion channels, like NMDARs, can be constructed from different subunits (a common example is AMPARs containing two subunits of GluA1 and two subunits of GluA2). Unlike NMDARs, however, AMPARs can also form channels of a single variety (e.g. AMPARs containing only GluA4). This leads to AMPARs being formed from lots of different possible combinations. It is likely that a receptor only needs one of its four subunits to be a variant for its properties to be affected.
We all have two copies of each of the GRI genes except for one – GRIA3. GRIA3 is unique in the GRI gene family as it is found on the X-chromosome. This means that while girls have two copies of GRIA3, boys only have one. This means that if a boy has a GRIA3 variant, there is no back-up copy, so it affects all of their GluA3 receptors and their symptoms are more severe than girls with the same variant. In fact, mothers who have a single GRIA3 variant can be completely symptom free because they have a spare copy, but can nonetheless pass on their unhealthy copy to their sons. Therefore GRIA3 variants are more common in boys, and, in fact, this means that GRIA3 disorder is the most common GRIA disorder overall.
The inhibitor Perampanel is the only prescribed drug directly acting on AMPARs and may help patients with GoF GRIA variants, especially those with epilepsy. Functional testing of the GRIA variant is essential before considering Perampanel, as it is not recommended for patients with LoF GRIA variants. There are currently no precision therapies for loss of function GRIA variants, and research is ongoing in this area.
Due to advances in DNA sequencing, and the increased systematic testing of children diagnosed with GRIA disorder symptoms, new cases of GRIA disorder tend to be identified in children. Nonetheless, there are adults known to have GRIA disorder, and there will be many more adults who remain undiagnosed and may never be genetically tested. Key details on the progression into adolescence and adulthood are limited, and understanding will grow as GRIA patients age.To help us understand more about the disease, if your child has received a diagnosis of GRIA1, GRIA2, GRIA3 or GRIA4 disorder, then contacting Dr. Allan Bayat in Copenhagen (abaya@filadelfia.dk) is a good first step. He is building a database of GRIA disorder patients to help understand the nature of these changes, how they produce particular symptoms and help identify the most effective treatments. For investigating the properties of individual variants, Dr. Ian Coombs at UCL in London (i.coombs@ucl.ac.uk) is an electrophysiologist who can identify if your child’s variant is LoF or GoF.