In 2012, Monica Weldon received life-changing news. Her four-year-old son Beckett, who had a history of developmental delay, was diagnosed with a rare genetic condition. Doctors discovered that Beckett had a variation in a gene called SYNGAP1.
At the time, Beckett was one of just six children in North America to be diagnosed with a change in this gene. SYNGAP1 variations had been linked to intellectual disability and, in some cases, autism. But little else was known about its impact. Doctors presented a grim but hazy picture of Beckett’s future.
Weldon resolved to change that. “The only way I knew how to cope, to keep from losing hope, was to build to something that wasn’t there,” she says.
Five years later, Weldon has built a thriving foundation called Bridge the Gap, dedicated to supporting SYNGAP1 families and studying the gene. She’s working with prominent scientists to figure out what happens when the gene goes awry and to come up with ways to temper those effects. In the last year, she has launched her own study, collecting information from her network of families. This kind of data can be vital to scientists, helping to focus their research and speed results.
Her efforts are already bearing fruit. Weldon will publish her first scientific paper, with her scientific collaborators, later this year. The study describes sensory perception and pain threshold in children with changes in SYNGAP1. She’s working with scientists on a number of other SYNGAP1 studies, including a project to screen potential therapeutic drugs.
“Everyone says this is moving so fast, but I want it to go faster,” Weldon says. “I am from Texas — we do everything big in Texas.”
A LONG ROAD
Like many children with rare disorders, Beckett had a long road to get to a diagnosis. Weldon noticed early on that Beckett wasn’t developing like his twin sister, Piper. He couldn't sit up or roll over when Piper could. “He was kind of like a floppy noodle,” Weldon recalls.
At his six-month checkup, Beckett was diagnosed with developmental delay. Doctors prescribed physical and occupational therapy, but his symptoms continued. Over the next few years, the family saw nearly a score of specialists and underwent a slew of tests, including CAT scans, MRIs, and EEGs.
At five years old, a 24-hour EEG test finally confirmed what his mother had suspected for several years. Beckett was having absence seizures, a type of brief seizure characterized by staring spells. “Once we realized he was having seizures, things started changing for us,” Weldon says.
Genetic testing at Texas Children’s Hospital revealed that Beckett had a change in SYNGAP1. At the time, only five other cases had been reported, and Beckett’s was the first known case at Texas Children’s. Physicians could tell Weldon very little about what the diagnosis meant for her son, except that it was linked to intellectual disability. “That's when I started my journey,” she says.
Weldon began reaching out to scientists and physicians who might have expertise in SYNGAP1. She started blogging about Beckett and his diagnosis, and other families with SYNGAP1 variations soon reached out. “That turned into a Facebook group, which turned into the organization that we have now,” Weldon says. She remembers feeling intimidated by the undertaking but felt she had no choice but to proceed. “This is a lifelong calling to help not just my son but others like him,” she says.
BRIDGING THE GAP
Children with SYNGAP1 variations can have a variety of symptoms — seizures, intellectual disability, and low muscle tone, as well as sensory issues and speech delay. The severity of each of these symptoms can vary widely from child to child. Weldon hopes that collecting detailed data through the foundation will help scientists and families understand why.
True to the name of her organization — Bridge the Gap — Weldon is constantly bringing together families, clinicians and scientists. She talks with researchers on a weekly, sometimes daily, basis. She regularly communicates with SYNGAP1 families through the Facebook page. She has brought families to visit research labs at Johns Hopkins. “It’s all about communication,” she says. “I think the family bond with physicians and scientists is what’s accelerating us. That constant drive to help one another is helping us to go faster. It's the only way we have gotten to where we are.”
In November 2016, Weldon and Gavin Rumbaugh, a neuroscientist at the Scripps Research Institute in Jupiter, Florida, organized an international conference in Texas, gathering 25 SYNGAP1 families from 10 countries together with scientists studying the gene.
During an awards ceremony one evening, families stood up and shared their stories and their gratitude with the scientists. The researchers responded in kind. “It was the most impactful meeting I have been to,” Rumbaugh says. “Science is a cool job, but this gives tremendous meaning to the job. I wish every scientist could have an experience like that. It’s changing the way I approach research.”
“I think scientists need to know why they are doing it, why they are writing all these grants, which sometimes get denied,” Weldon says. “When you see a child who will benefit from the work, that changes the whole game.”
SEARCHING FOR TREATMENTS
Richard Huganir, a neuroscientist at Johns Hopkins University, began studying SYNGAP1 in the 1990s, long before it had been linked to intellectual disability or autism. The gene produces a protein found in the very tip of synapses, the connections between neurons. The SYNGAP1 protein helps to strengthen synapses during learning. Disrupting the gene in mice can lead to serious learning and memory problems and visible changes at the synapse.
Children with changes in SYNGAP1 usually have one normal copy of the gene and one copy that is missing or compromised. These changes tend to be de novo, meaning children did not inherit them from their parents. The specific genetic change varies from child to child, which might help explain why symptoms can be so diverse. Some changes are small, altering a single letter in the gene, and can have mild effects. Others are profound, disrupting the gene completely.
Huganir and collaborators have developed new methods to study the impact of SYNGAP1 changes. They engineer the changes found in people into brain cells growing in a dish. They then measure how those changes alter neuronal connections. Huganir’s team is using this system to search for drugs that fix these problems. One drug showing early promise is lovastatin, a cholesterol-lowering drug that also effects neuronal connections.
Rumbaugh is searching as well for drugs to treat SYNGAP1-related issues. He and others have shown that boosting SYNGAP1 in mice missing the protein can help reverse memory problems and restore normal synapses. Rumbaugh and collaborators have developed a method to search for drugs that raise SYNGAP1 levels. In June 2017, Rumbaugh’s team was awarded a $2 million grant to test 20,000 compounds that have been shown to be safe in humans.
Both Huganir and Rumbaugh began as basic scientists, meaning they focused on how the brain works rather than on links to specific conditions. They are excited to see their basic research acquire this new dimension.
“It’s been inspiring; it takes the science to a different realm,” Huganir says. He adds that SYNGAP1 provides an excellent example of how basic science can have a huge impact on medicine. “We had 20 years of research on SYNGAP1 that we can use to help guide therapeutic research,” he says.
Rumbaugh is one of the first scientists that Weldon reached out to when she began her quest, and he is a founding member of the foundation’s scientific advisory board. Interacting with families has definitely shaped his research, he says. “Getting to know families and interacting with kids makes the research more rewarding, but you also get insight that you can only get from interacting with them.”
For example, a number of families have reported unusual sensory behavior, a link that hadn’t been reported in the scientific literature. “They universally said that children have bizarre behaviors related to touch and feel,” Rumbaugh says. “They seek out textures, rub their faces on the carpet. They love to be touched and hugged.” Researchers can now examine whether mice with SYNGAP1 variations show similar issues and how that might contribute to learning and memory problems.
Rumbaugh also uses parent feedback to shape drug studies. For example, one seizure drug had developed a bad reputation among SYNGAP1 families because children tended to do poorly on the drug. But one family had taken extensive notes during treatment and reported that it worked well at low doses. “That gives us motivation to test subthreshold doses in the lab,” Rumbaugh says.
Weldon is now delving into the research arena herself. She won a grant from the National Organization of Rare Disorders, in partnership with the Food and Drug Administration, to create a database of symptoms and other information from SYNGAP1 families.
For example, the foundation is collecting information on the medications children take to treat seizures and other issues, along with positive outcomes and negative side effects. Weldon hopes the data will help inform future clinical trials of SYNGAP1 treatments by highlighting which symptoms to measure. “All of it is important to get to the researchers to try to narrow down the direction they need to go and come up with the best theories and protocols and projects,” she says.
Weldon officially launched her study on Christmas Day 2016 and has since enrolled 70 participants. “That was the best Christmas present ever,” she says. She expects that number to grow as more children are diagnosed with changes in SYNGAP1.
SYNGAP1 variants were thought to be quite rare when Beckett was diagnosed. To date, about 250 people have been diagnosed with SYNGAP1 variations. But genetic testing for SYNGAP1 is on the rise. SYNGAP is one of the genes assessed in SPARK genetic testing. Based on studies of developmental delay, scientists estimate roughly 200 new cases will be diagnosed per year. Rumbaugh says it will likely take years to really understand the frequency of SYNGAP1 changes.
Currently, an average of two new families per week sign up for Bridge the Gap. Weldon hopes that enhanced genetic testing will boost that figure even higher. “The more we get the word out to physicians, the easier it will be to get genetic testing,” she says. Weldon has been working with different genetic testing companies to include SYNGAP1 in their gene panels — genetic tests that assess a number of genes linked to a specific condition — for epilepsy and autism.
She hopes that SYNGAP1 studies will help her son and the families she works with, but she thinks the research will have a much broader impact as well. “I believe our kids are a cornerstone to understanding other diseases that are similar to ours,” Weldon says. “This is bigger than just our kids.”
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