All About GRIA Disorder

GRIA Disorder is part of a larger family of genetic diseases related to ionotropic glutamate receptors and is caused by a change in one of four GRIA genes including GRIA1, GRIA2, GRIA3, and GRIA4. These genes contain the code to create AMPA receptors. GRIA1, GRIA2, and GRIA4 variants are inherited in an autosomal dominant pattern, while GRIA3 is X-linked. X-linked intellectual disability disorder associated with GRIA3 is also sometimes referred to as Wu syndrome. X-linked variants are unique because they are much more likely to occur in genetic males because they only have one X chromosome. Therefore, if they receive one copy of an X-linked variant, they will show the trait. For GRIA3, there have been numerous X-linked cases in males, where the variant was inherited from their mother, and a few de novo cases in females. 

GRIA variants have been associated with intellectual disability and ASD. In addition, some GRIA patients may experience behavioral difficulties including features of autism, reduced attention span, anxiety, and hypersensitivity to stimuli. 

We do not have a clear sense of how common GRIA Disorder is yet because so few patients have been reported in the registry and scientific literature.  

Perampanel (Fycompa) is the only widely licensed drug available that specifically targets AMPARs. AMPARs are ionotropic glutamate receptors that act together with NMDARs to produce synaptic plasticity, which is the ability of synapses (the connections between 2 neurons) to strengthen or weaken over time and promote learning and memory. Perampanel is a non-competitive antagonist. This means that perampanel binds to a different site from glutamate (Faulkner, 2017). It works as a non-competitive inhibitor, so it prevents the normal excitatory response to glutamate from occurring without blocking glutamate from binding to the receptor (Faulkner, 2017). 

Perampanel has been approved in the United States to treat partial-onset seizures in patients 4 years old and up (Piña-Garza et al., 2020). It has been approved as an additional treatment (adjunctive) for primary generalized tonic-clonic seizures in patients 12 years old and up (Piña-Garza et al., 2020). 

Perampanel is a potentially beneficial treatment option for patients with uncontrolled epilepsy and has been shown to reduce seizure frequency in some patients. Some patients with GRIA Disorders have been prescribed perampanel (off-label), though there are currently no clinical trials focused on perampanel in GRIA Disorder patients.

CureGRIN plans to work with researchers, clinicians, biotechnology companies, and pharmaceutical companies to encourage and help facilitate the development and testing of treatments for GRIA Disorder patients.