GRI Clinic Leads the Nation in Advancing Care for GRI-Related Disorders

Imagine trying to solve a puzzle without the context of the full picture. That was the challenge facing families and clinicians caring for children with what's now known as GRI-related disorders. This extremely rare group of genetic conditions affects how the brain and nervous system work, and they’re caused by variation in genes that make ionotropic glutamate receptors. For decades, doctors saw and treated the individual pieces — epilepsy, developmental delays, autism, behavioral challenges and movement disorders — but they didn't always know how they were connected.  

In 2007, things began to change. Researchers discovered that mutations in GRIN genes were associated with intellectual disabilities, developmental delays and severe epilepsy. Over the next few years, clinicians began sequencing genes in children with similar symptoms and identified comparable types of structural mutations within GRIA, GRIK and GRID gene groups. 

As the understanding of GRI-related disorders grew, so did the need for specialized care from experts who understood these rare and complex conditions. In 2023, with support from the GRIN2B Foundation, Children's Hospital Colorado opened the first GRI Clinic in the United States — a milestone in the treatment of GRI-related disorders. And three years later, the clinic continues to contribute to advancements in care. 

Building a Center of Excellence for GRI-related disorders  

Kristen Park, MD, a preeminent pediatric epileptologist, leads the clinic and provides individualized care for patients with GRI-related disorders, including GRIN, GRIA, GRIK and GRID. The clinic, which is only one of two in the country, delivers best-in-class clinical care through a  multidisciplinary approach. The team at the GRI Clinic works together with families and includes epileptology, neurology, genetic counseling, social work, developmental pediatrics and nursing.  

"It's a clinic where everyone understands what's happening," Dr. Park says. "Many of our families are used to having to explain GRI disorders to their care teams. But we all know the intricacies. We're starting to make more meaningful connections of what that means." 

The GRIN2B Foundation designated the GRI Clinic as a GRI Center of Excellence. This designation recognizes not only the clinic's intentional model of care but also its commitment to research, data sharing and collaboration to improve the lives of those affected by GRI-related disorders. 

Advancing GRI-related disorder research through global collaboration 

Because GRI-related disorders are so rare, Dr. Park says international partnerships are essential to accelerating discovery and improving patient care. The GRI Clinic collaborates with groups at Emory University and research centers in Germany, the Netherlands and Italy.  

"How can we bring these patients, who are scattered everywhere across the world, together to learn more about their diagnosis?" Dr. Park says. "If we put all of our resources together, we can get enough numbers to really draw some reasonable conclusions about the data." 

Recently, Dr. Park contributed to a paper exploring memantine treatment — a current medication for Alzheimer's disease — for 34 individuals with GRIN. The group was divided into those with gain of function genetic variants, meaning the ionotropic glutamate receptor is overly active, and those with loss of function, meaning the receptor wasn't active enough.  

Among the 19 people with pathogenic gain of function variants: 

• 74% benefitted from memantine 
• 71% showed behavioral improvements 
• 50% showed developmental improvements 
• 39% had fewer seizures.  

The participants with loss of function variants did not benefit as much from the treatment. While the results suggest memantine may be effective for certain patients, it also provides researchers with valuable clues about how genetic subtypes respond to treatment and where future studies should focus.  

Because of the GRI Clinic, researchers at Children's Colorado and across the globe are making significant strides in understanding these disorders. Dr. Park believes this is only the beginning.  

"My hope is that the clinic can be truly iterative, meaning that the lessons learned from each visit can help the next child receive better treatment, and that patterns will emerge to stimulate the next round of research questions. In this way, the reach of the clinic extends beyond the walls to all affected families," Dr. Park says.