"It's a slow-moving train wreck," Mike Graglia says about his 12-year-old son Tony's rare genetic disease with no cure.
Caused by a tiny fluke of nature—a mutation in a gene known as a SYNGAP1—the non-hereditary condition can lead to intellectual disabilities, epilepsy, autism spectrum disorder, insomnia, hypotonia (low muscle tone), chronic digestive issues, and severe mood and behavioral disturbances.
"For many parents, it's a marriage breaker," says Graglia, who talks to and supports families every day through the foundation he established, SynGAP Research Fund, after Tony was diagnosed eight years ago. "My wife and I are still married, but it hasn't been easy. How could it be?"
Graglia earned a master's degree in 2003 from Johns Hopkins' School of Advanced International Studies and showed up in a JHU sweatshirt for his Zoom interview. "I'm still a big Hopkins' fan," he says. Today, he lives with his family in California and takes part in a research initiative of neuroscientist Richard Huganir, a Bloomberg Distinguished Professor at Johns Hopkins who says his lab is within five years of a potential cure that gets at the root of the problem: repairing the faulty gene.
"We've been able to make significant progress with funding from the National Institutes of Health, but the federal government's cuts put everything at risk and cast a dark cloud over our lab—and over the entire SynGap1 community," says Huganir, who directs the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins School of Medicine.
Video credit: Patrick Ridgely / Johns Hopkins University
SYNGAP1-related disorders are among the 7,000-plus rare diseases in the world that roughly 300 million people contend with daily, The Lancet Global Health reports. Changes to NIH funding streams, however, especially threaten the rare-disease community, in part because rare diseases are less frequently researched or taken under the mantel of private companies working on treatments or cures for more common medical conditions. As Paul Melmeyer, a vice president for the Muscular Dystrophy Association, describes it in a recent Forbes article: "There's a lot more funding in cancer and Alzheimer's than there is for that rare genetic disease that might only have two or three research projects funded by the NIH across the entire United States. Those are the areas we're especially concerned with, because if those go away, if the university can't afford to run them anymore, then disease research in those areas halts entirely."
Huganir and his lab of research associates, postdoctoral fellows, and graduate students, along with Tony's family and others with SYNGAP1-related disorders, fear the cuts will slow or stop progress that has been decades in the making. In 1998, for instance, Huganir and another neuroscientist at the California Institute of Technology, Mary Kennedy, discovered the SYNGAP1 gene on chromosome 6. Their breakthrough led to other breakthroughs, including the realization that SYNGAP1 plays a leading role in how the brain forms its vast network of synapses, which are vital to human brain function.
Microscopic junctions that enable our nerve cells (or neurons) to communicate with each other, synapses function like traffic control operators. They direct our brains to work with and perform endless behaviors and tasks in our bodies, from processing and connecting information we encounter to goading a muscle or gland to spring into action.
As many as 10,000 synaptic connections exist for every single one of the billions of neurons in the human brain, Huganir says. When those trillions of synapses fail to form properly, problems like Tony's can ensue.
It hinges in large part on that one gene.
"Mutations in the SYNGAP1 gene affect the production of the SynGAP protein, which in turn affects our brain's ability to absorb information and adapt as needed to various circumstances and environments—what we refer to as neural plasticity—and it interferes with learning and memory," Huganir explains. "Typically, kids and adults with SYNGAP1 mutations present with seizures, developmental delays, and cognitive impairment."
A wide range of mutations can exist in the SYNGAP1 gene resulting in the loss of SynGAP1 function. This variation can make diagnosis, which requires genetic testing, tricky. And Huganir says he believes many kids and adults are missed, making the spectrum disorder less rare than many people realize. "Newer research estimates that hundreds of thousands, if not a million, people [worldwide] have these mutations," he says. "That's about 1% of intellectual disability."
SYNGAP1-related disorders, then, are still rare, "but they're among the most prevalent rare disorders, and they have a major general genetic association with autism," Huganir says. Autism affects roughly one in every 36 8-year-old children in the U.S.—a number that has risen sharply over the last two decades, owing to factors such as better awareness and screening tools and broader diagnostic criteria, according to a CDC report that researchers at the Bloomberg School of Public Health helped to compile.
As Huganir sees it, his research on SynGAP contributes to the world's understanding of autism spectrum disorder (ASD) and other conditions linked to the SYNGAP1 gene. And the technique he's working on to treat kids like Tony could potentially help those with other SYNGAP1-related conditions.
Known as antisense oligonucleotides, or ASOs for short, the new technique involves injecting a small piece of DNA into the cerebral spinal fluid of a child's spinal cord. The DNA then targets and binds to messenger RNA (mRNA), which instructs the body to produce the missing SynGAP protein.
"The ASO technique became famous about five years ago because it totally cured a group of kids with spinal muscular atrophy, a genetic neuromuscular condition caused by a lethal genetic mutation," Huganir says. "Normally, kids with this condition die by the age of 2, but this treatment saved the lives of those in the clinical trial who received it, while kids in the placebo group sadly died."
Image caption: Richard Huganir, center, with Ulrich Mueller
Image credit: Will Kirk / Johns Hopkins University
Huganir's approach aims to fix the underlying cause, rather than simply treating the symptoms. Currently, treating symptoms is the only form of therapy available to individuals with SYNGAP1-related disorders.
"I put drugs in my kid's mouth for seizures, for behaviors, to make him sleep, to make him poop—and that's on a good day," Graglia says. "On a bad day, I'm adding medication to interrupt aggressive behaviors or seizures.
"It's hard to imagine doing this forever, but unless there's a cure, that's the reality," he says. "[SynGap] destroys families, it destroys lives, and the patients themselves are suffering mightily."
In the clinic
Constance Smith-Hicks, a neurologist and research scientist at Kennedy Krieger Institute, treats more than two dozen SynGap1 patients and knows well the disorder's enormous burden on families and individuals. "There's no single treatment drug, and it takes a lot of trial of error … and an awareness of polypharmacy," or how drugs interact with each other, given that patients can easily take as many as 10 different medications, Smith-Hicks says. "We usually start by treating the epilepsy, if seizures are present, and even for kids on epilepsy drugs, breakthrough seizures can occur, so we tweak and refine."
Roughly 50% of kids with SYNGAP1-related disorders develop ASD, and 70% to 80% of those with behavioral challenges go on to exhibit what Smith-Hicks describes as "self-interest behaviors like head-banging, pinching themselves, and other [actions] that can cause bruising," she says. Families need to safeguard their houses, and some, for example, end up taking everything off their walls to make the environment as amenable as possible, she explains.
Moreover, SYNGAP1-related disorders often disrupt sleep, and "when a child isn't sleeping, then the parents aren't sleeping, and most of us don't behave well when we're lacking in sleep," Smith-Hicks says.
Gastrointestinal problems like constipation can be extreme, and kids with the condition may not want to eat fruits and vegetables, drink water, or do other things to improve digestion.
In her clinic, she takes an interdisciplinary approach, with a treatment team made up of specialists in genetic counseling, behavioral and clinical psychology, nursing, and social work. Having a social worker is key, she says, because caring for a child with SYNGAP1-related disorders takes work and costs money.
Graglia agrees. Through his foundation, the SynGAP Research Fund, he not only raises money to support efforts toward a cure but also counsels caregivers in the trenches. "I talk to a lot of single moms who are worried about what will happen when their son or daughter grows bigger and stronger and decides to bolt or have a temper tantrum in public," he says.
"No matter how much you love a kid," Graglia continues, "if they've just broken your tooth or given you a bloody nose or bitten through your clothing, … it's going to tax your sanity."
Hope through research
Smith-Hicks collaborates with Huganir and hopes to someday administer the ASO treatment he's working on to restore production of the SynGAP1 protein—and thus restore neural plasticity and start the process of rewiring the brain.
Research is the only way to achieve that, she says, and funding cuts and pauses from the NIH could cause a real setback.
"In the world of Rett syndrome, another rare genetic disorder that I treat, we identified [the condition] in 1965; we identified the gene in 1999; and then in 2003, we had our first FDA-approved treatment," she says about a disease that interferes with brain development and derails motor skills (including the ability to eat) and language. "That's quite some time, but we've been able to build on the knowledge gained not just from the Rett syndrome clinical trials but also many other rare disease clinical trials."
Federal research dollars have enabled the medical community to better understand how diseases progress over time and to identify the best times to intervene, according to Smith-Hicks. They've allowed researchers to map the genome and determine the genetic biomarkers of countless diseases—"knowledge that is critical to what happens on the clinical side, such as diagnosing a disease, monitoring disease progression, and evaluating the effectiveness of a treatment," she says.
NIH dollars also support clinical trials, along with the checks, balances, and safety measures that pave the way. This includes support for clinicians to work collaboratively with researchers and to receive feedback from patient advocacy groups, the FDA, and the pharmaceutical industry, all of which are necessary in the lead-up to a clinical trial, Smith-Hicks says.
For Huganir, the stakes are high for patients and families—and for our country's standing as a global leader in research and development. "What makes American science so great is the federal government's investment partnership with universities that has existed for 75 years," he says. "Nowhere in the world matches that, including China. But it's all at risk."
Graglia says he's monitoring the political situation closely, in between caring for Tony, a regimen that involves diapers and physical and occupational therapy appointments and pharmacy pick-ups and wrangling with his health insurance company—with no end in sight.
"We don't want our genius-level scientists and postdocs worrying about job security and how they're going to pay their mortgage or rent," Graglia says. "We need them working around-the-clock and laser-focused on medicines for our kids.
"Because SynGap1 is a horrific disease."
And a cure may be on horizon.
Jeff Coller, a Bloomberg Distinguished Professor of RNA Biology and Therapeutics at Johns Hopkins and the inaugural director of the university's RNA Innovation Center, is also working on a novel treatment for SYNGAP1-related disorders and other rare genetic diseases. Read his story about his work.
