RARE Daily

Grant Seeks to Develop Treatment Strategies for Autism and Schizophrenia Associated with DiGeorge Syndrome

April 3, 2023

Rare Daily Staff

The Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, has awarded a five-year, $3.4 million grant to Anthony-Samuel LaMantia, a professor at the Fralin Biomedical Research Institute at Virginia Tech, to develop new treatment strategies for autism and schizophrenia associated with the rare neurodevelopment condition DiGeorge syndrome.

DiGeorge Syndrome, also known as 22q11.2 deletion syndrome, is caused by a small missing piece of the 22nd chromosome. The condition causes palate abnormalities, heart defects, immune dysfunction, and esophageal/GI issues, as well as debilitating neuropsychiatric and behavioral challenges. Children with the condition also experience withdrawn behavior, ADHD, cognitive impairment, and autism spectrum disorder that affect communication and social interaction. Later in life, they are at an increased risk of developing mental illnesses such as schizophrenia.

LaMantia’s lab, one of a handful in the world working on this problem, has studied DiGeorge syndrome for more than two decades. The lab dives deep into how the brain’s circuits are constructed to develop a precise understanding of the syndrome’s causes.

“I think 20 years of research has provided a foundation for thinking about this disease differently in the clinic,” LaMantia said. “It’s a neurodevelopmental disorder, and it’s disrupting very specific, identifiable steps in development of the brain. And we’re really trying to now look at one of the last steps of brain development that we think is the most likely to be accessible to making adjustments without damaging other things.”

LaMantia believes the mitochondria—the powerhouses of cells—are central to disrupting brain development in DiGeorge syndrome. In a typically developing brain, the mitochondria in neurons in the cerebral cortex have enough energy to create long-distance connections to other parts of the brain and turn the circuits on and off to ensure everything is working properly.

In DiGeorge syndrome, though, the mitochondria are oxygen-starved and lack the energy to make necessary connections. The reason for this disruption can be traced to several genes in the region of chromosome 22, which is deleted in DiGeorge syndrome. The imbalance of having only half of the required amount of these genes, the proteins they encode, and the support for mitochondria they provide, underlies a failure to make sufficient numbers of connections during brain development, and a dysfunctional system.

While many of the syndrome’s impacts occur before birth, or before the disease can be diagnosed, the mitochondrial deficit that disrupts making these final connections occurs late enough in brain development to allow for intervention.

“If you’re going to fix it, that’s probably the only place that is viable to fix it, and without causing other problems in the process,” LaMantia said. “It’s fortunate that these are mitochondrial changes, because you can support mitochondria through relatively simple and very safe means, including dietary supplements or more precisely-targeted drugs.”

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