CHOP Researchers Work to Advance Understanding of HI/HA

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common form of congenital HI. The genetic cause, a mutation in the glutamate dehydrogenase (GDH) protein, was first identified at CHOP in 1997. Our team continues to pioneer exciting and impactful research to advance understanding of this disorder.

Understanding neurological problems

Individuals with HI/HA syndrome often have seizures, learning disabilities and behavioral disorders such as attention-deficit/hyperactivity disorder (ADHD). The reason why the brain is affected in HI/HA is not fully understood.

As a first step to tease out the “why” behind various features of HI/HA syndrome, we are creating a mouse model to study GDH mutations in different organs, including the brain. We are also using a new magnetic resonance imaging (MRI) technique that can measure a chemical called glutamate in the brain, which can help us understand how the mutated GDH protein in HI/HA syndrome affects brain function.

By combining this new MRI technique with other specialized studies, we aim to create a detailed description of the neurodevelopmental features of HI/HA syndrome — and by doing so, uncover their cause. Most importantly, understanding the cause will allow us to develop tailored treatments.

Exploring new treatment options

Currently, the only available treatment for HI/HA syndrome is diazoxide. Unfortunately, diazoxide has no effect on the elevated ammonia levels, seizures or developmental differences experienced by patients with HI/HA syndrome.

Early-stage research in mice has shown that vitamin E works directly on the mutated GDH protein. These preliminary results suggest that vitamin E may be an effective treatment for HI/HA syndrome.

However, before vitamin E can be used for treatment, it needs to be determined to be safe and effective in humans. Right now, our team is working to see if vitamin E is safe and well-tolerated in patients with HI/HA syndrome. If so, our next step will be to evaluate how effective it is. We are hopeful that this could be a new therapeutic option for individuals with HI/HA – one with the potential to prevent and treat not only the low blood sugar, but also the neurologic symptoms associated with this condition. 

This is exciting new research has been made possible by grants from the Penn Orphan Disease Center Million Dollar Bike Ride Grant Program, the Penn ProDev program, CHI HI/HA grant program, and by the generous contributions of families affected by this condition.

Learn more about how you can contribute and find more details about ongoing HI/HA studies. If you have questions about our hyperinsulinism research, please contact us at HIResearch@email.chop.edu.