Families and Researchers Come Together to Seek Cures

UNC Eshelman School of Pharmacy researchers use CRISPR for insights into rare disease

Story by Ryan McDaniel | Published November 7, 2022

When Kim Ventarola’s son, Dominick, did not pass his newborn hearing test, it was her first sign that something was off. Then, between the age of two and four months, Dominick’s head grew rapidly, causing his pediatrician great concern. After a scan to rule out hydrocephalus, Kim and her family began consulting with various medical experts; first an audiologist, then a neurologist, then a cardiologist. “By the time Dominick was a year old we had over six specialists. I knew something wasn’t right,” Kim recalls. “I just kept pushing. All of the doctors kept saying ‘let’s just wait and see. He’s meeting his milestones, it’s just a little delayed.’ But, as a mom, I knew something just wasn’t right.”

Around the same time, Christal Delagrammatikas was in the hospital with her son, Yanni, after his second seizure at age seven. Like Dominick, Yanni had an enlarged head and had not met his infant development milestones in the expected timeframe.

The answer as to what was going on with their children came to both women after geneticists ordered exome sequencing: Dominick and Yanni both had a rare genetic disease, Malan syndrome.

Malan syndrome, which was only formally described in 2010, is identified by a mutation in the Nuclear Factor One X (NFIX) gene. This genetic change alters the proteins created by the NFIX gene, causing symptoms such as tall stature, low muscle tone, mobility issues, seizures, severe scoliosis, intellectual disability, and other physiological and behavioral complications.

“The biggest challenge for Yanni is severe anxiety,” says Delagrammatikas. “Getting out of our house, getting him to school… He wants to go outside. He wants to participate. He’s a very social, friendly child, but that anxiety is so crippling.”

Kim’s son, Dominick (left), and Christal’s son, Yanni (right)

Ventarola faces different struggles with Dominick, who is six years younger than Yanni, “He is severely visually impaired, so he has been using a white cane since he was about 26 months old. Unfortunately for Malan Syndrome, there’s no research being done now on vision, though it’s really affecting the everyday lives of children with Malan syndrome.”

Christal and Kim, seeking both answers and a support network, found each other through a Facebook support group for people with Malan syndrome and their families. While they now had the network of support they’d hoped to find, the two wanted to do more. Along with fellow parents Brandilyn Johnson and Bethanne Durell, they founded the Malan Syndrome Foundation in 2019. The Foundation’s mission is to improve the lives of individuals and families affected by Malan syndrome in the global community through support, outreach, and research. “Parents are instrumental in driving research foundations towards therapies,” says Christal.

To support research into Malan syndrome, the Foundation has recently awarded the UNC Eshelman School of Pharmacy a two-year grant totaling $30,000. The study will be led by Erin Heinzen, associate professor in the Division of Pharmacotherapy and Experimental Therapeutics, and Nate Hathaway, director of UNC’s CRISPR Screening Facility and associate professor of chemical biology and medicinal chemistry. Using CRISPR technology, Heinzen and Hathaway seek to identify all genes in the genome that alter how much of the NFIX protein is made. In doing so, they hope to find ways to increase the amount of protein produced in individuals with Malan syndrome.

“This will be the first neuronal cell screen at this scale at our facility, and the process we’ll be applying in this study is exactly what CRISPR technology was intended for,” explains Hathaway.

Both Christal and Kim are hopeful for where this research can lead. “This research is going to show us what genes and pathways affect NFIX protein expression and what we could potentially target with therapeutics, improving some of the symptoms our kids deal with on a daily basis,” Christal says. “If I can improve my son’s anxiety to where he can go outside, go to the swimming pool, go to school without having this overwhelming anxiety… That would be huge. That would open up his life.”