The disease is rare, with only 100 children officially diagnosed in the United States. For affected families, connecting with a UF scientist was the lucky break needed to start unlocking the secrets of Smith-Kingsmore Syndrome.

by Liesl O’Dell (BSJ ’92)

Jack Groseclose was 15 years old when his parents received the news. They had waited all that time for any insights into Jack’s many symptoms. After all, this condition didn’t even have a name – Smith-Kingsmore Syndrome (SKS) – until their son was 11.

It was December 2018 and Jack’s sleep doctor in Cincinnati, Ohio, had just read a research article by Andrew Liu, a University of Florida biochemistry and molecular genetics scientist credited with discovering which gene controls humans’ circadian rhythms (sleep/wake cycles). After talking with two other doctors – Jack’s geneticist and neurologist – the sleep doctor picked up the phone, found Liu in his lab at UF and asked if Liu’s recent discovery could help Jack, who had only slept a couple hours a night since birth.

His sleep deprivation over the years was a drain on the whole family. His parents had been tracking Jack’s sleep with a FitBit, since Jack often taps one hand with the other when he’s awake, which the device tracks as steps. Their son, said Kristen Groseclose, Jack’s mother, was sometimes logging more than 20,000 “steps” a night.

His tapping, along with an inability to communicate, resulted in a diagnosis of severe Autism early on. But in 2013, SKS was officially recognized as a mutation in the mTOR gene that causes a wide range of challenges, the most common being intellectual disability, developmental delay, large brain size and seizures. Only about 100 children, including Jack, have been officially diagnosed with SKS so far in the U.S. Just as Autism is measured on a wide spectrum, SKS-affected children also range from high functioning to severely affected.

Liu told Jack’s doctor he hadn’t heard of SKS, but he wanted to help them find the answers they and Jack’s family needed. In the two years since that phone call, Liu’s research has proven vital to everyone in the SKS community around the world.

When a Child Has Disabilities

For Jack’s parents, living without answers has been their normal. They knew something “wasn’t right” with Jack at his 1-year-old checkup, recalls Kristen, who lives with her husband, Mike Groseclose, in a Cincinnati suburb. But their doctor advised they forgo any genetic testing because “the science isn’t there yet,” she recalls.

Instead, the parents grew to rely on what they know: Jack is a loving, caring child with special needs. He has a strong sense of humor and a deep sense of gratitude. Strangers can see all of this, too.

“Once when we were at the mall at Starbucks, we were laughing about something,” Kristen said. “A woman came up to me and said, ‘Everyone is looking at you and is enjoying the way you interact.’ … Situations like that make us feel like special-needs ambassadors.”

The Groseclose family, (from left) Mike, Jack and Kristen, didn’t learn that Jack’s group of physical and mental disabilities had a name – Smith-Kingsmore Syndrome – until he was 15 years old. SKS was officially named in 2013.

While Kristen says her family has lots of positive interactions with strangers, their public outings also include plenty of challenges.

“The world is not set up for people with disabilities,” Kristen explained. “We have to pick our battles. Would Jack love to go to watch a ballet? Sure, but he makes verbalizations and in a quiet environment that can be disruptive. People look.

“We have to think ahead, too. He wears diapers, so we can’t take him anywhere with a Port-A-Potty. We can’t be out too long,” she said. “But there’s nothing unique in the challenges we face with SKS. Anyone who has a child with significant needs knows.”

Eric and Nazira Kelly in Fayetteville, N.C., agree with those sentiments. Their 4-year-old son, Ezra, was diagnosed with SKS in August 2019 after three rounds of genetic tests. Non-invasive prenatal screenings hadn’t shown any abnormalities, but at 2 weeks old, Ezra developed light-colored splotches on his skin. When he was 4 weeks old, Eric and Nazira noticed that his head started to grow disproportionately larger. And when Ezra started having grand mal seizures at 6 months old, doctors intensified their search for possible causes.

Nazira, a labor and delivery nurse, says despite her medical experience she and her family felt overwhelmed when they entered the world of SKS – a menagerie of medical terms and acronyms, physical therapy, occupational therapy, tests and more tests. They found comfort, she says, in the small SKS Foundation community on Facebook. That’s about the time Kristen and Mike Groseclose launched the Smith-Kingsmore Syndrome Foundation with other families to raise awareness and money for scientific research, and planned the first SKS family conference in Cincinnati. Kristen serves as president.

“They embraced us,” Nazira said of the other SKS families. At the conference, Nazira and Ezra met with several pediatric specialists, who talked with them and revealed more about the specific SKS traits in Ezra. Back then there were 48 different genetic variants of SKS. As research continues, though, the number of genetic variants is growing. Nazira says she walked away from the conference with a new perspective.

“We met a variety of children – all ages and young adults – who had been waiting their whole life for a diagnosis,” says Nazira. “One girl was 22 before they had a diagnosis. Those two years and 11 months that we didn’t have a diagnosis seemed like an eternity for us.”

Nazira, who has developed a strong friendship with Kristen Groseclose, says her whole family has adjusted to their new normal with Ezra. That means managing Ezra’s special needs and his seizures.  Nazira and Eric now understand that the seizures, which happen while Ezra is asleep, are triggered when his brain shifts from one sleep stage to another, usually during the first or last hour of bedtime. During his seizures, each family member has a task. Even Ezra’s 6-year-old sister, Zara, knows her job: stroking Ezra’s hair and telling him calmly and sweetly, “Don’t be afraid.”

Ezra’s seizures typically last five to seven minutes, but he’s had a couple that have lasted 20 minutes and required ER intervention. No matter the length, Nazira says each seizure is scary.

“I’ve seen some of my adult women patients have seizures due to pre-eclampsia,” Nazira said. “But the first time Ezra had a seizure it was a terrifying event. Everything I knew about being a nurse went out the window. It was a grand mal seizure. That’s our big challenge – seizures. Kristen’s big challenge [with Jack] is sleep.”

Nazira, who has developed a strong friendship with Kristen Groseclose, says her whole family has adjusted to their new normal with Ezra. That means managing Ezra’s special needs and his seizures. Nazira and Eric now understand that the seizures, which happen while Ezra is asleep, are triggered when his brain shifts from one sleep stage to another, usually during the first or last hour of bedtime. During his seizures, each family member has a task. Even Ezra’s 6-year-old sister, Zara, knows her job: stroking Ezra’s hair and telling him calmly and sweetly, “Don’t be afraid.”

Tailoring Treatment

A “central clock” exists in virtually every cell in the human body. For Liu and his research team, learning about SKS has enhanced his initial understanding of the mTOR gene. Whereas he once understood that the gene modifies that internal clock, resulting in sleep pattern disturbances, seizures and other health issues, he has since learned that the gene influences each cell’s nutrient and energy status, cell growth and division, cancer predispositions, aging and more.

“The mutation of this gene changed the fundamentals of cell biology,” said Liu, an associate professor in the Department of Physiology and Functional Genomics in UF’s College of Medicine. “Think of it as an energy balance that affects every cell. When it’s tipped off balance, it affects many things … We’re looking into the biochemistry of how the mutations change the activity of the protein and the cell’s behavior.”

Jack Groseclose is one of only about 100 children in the U.S. who have been officially diagnosed with Smith-Kingsmore Syndrome. UF scientists are working on medicine dosing guidelines for SKS children who, like Jack, sleep only a few hours each night.

While a medicine developed to help correct sleep patterns has worked for some SKS children, it has brought about extreme sleep in others. Jack went from sleeping only a couple hours a night on his own to about 15 hours per day on the medicine.

“Jack had fewer headaches with that medicine,” Kristen Groseclose said. “But when he was sleeping 14, 15, 16 hours a day he was more unhappy than when he pulls all-nighters.”

Liu and his UF research team were able to find a happy medium that Jack and other families needed by tailoring the medicine dose to specific gene mutations. At the time Liu got involved, about 20 different mutations were known to science; today, more than 60 have been identified. Liu’s team has developed a pipeline to test the biochemical activities of the mutated proteins and their impact on cell behavior. This pipeline means future testing will happen faster. Liu says his team aims to test all the mutations currently known, and others as they are discovered.

“All the mutations are not the same, and some children have more than one,” Liu said. “They respond to drugs and nutrients differently, too. That’s a lot of possible variations.”

To speed up Liu’s dosing guidelines project in 2020, the SKS Foundation raised about $60,000 in donations and created a fund at UF. Liu used the gift to support a full-time post-doctorate researcher in his UF College of Medicine lab. The fund also fuels work that aims to improve the quality of life for children with SKS. This year, the SKS Foundation pledged to duplicate its efforts, aiming to raise $60,000 by December to support Liu’s post-doc again. At the time of this article, the foundation received $46,000 of that goal.

“So many families from around the world pulled together to make this possible,” said Kristen Groseclose, “because without their efforts, we couldn’t have accomplished any of this – in addition to Dr. Liu and his team of course!”

Hope for Maternity Screening

For Liu, his research has become personal. He’s met with scores of patient families so far and knows many by name. He talks about SKS children who have died for unknown reasons, the families who struggle because they’re functioning on little sleep, and the other scientists who, like himself, are working to find SKS solutions as fast as they can.

“I don’t know how these parents lead their lives, to be honest,” said Liu, who with his wife, Haiyan Xu, a UF College of Medicine researcher, has three daughters – two in college and one in 7th grade. “There is no inherited gene mutation from the parents. This is a mutation in the early stages of fetal development that results in children who can’t communicate well, some who can’t eat by themselves, who have intellectual disabilities. It’s just a lot.”

Liu says he and his team are building an SKS knowledge base, which could improve the precision of treatments on an individual patient or mutation. They also aim to one day provide a maternity screening test that will alert doctors to early gene mutations so babies can be treated early, possibly in utero, before SKS’s most severe symptoms – seizures and Autism – develop.

“If we know … we can treat them in the early neonatal period before the horrific damage occurs,” Liu says. “We’ve seen this in many other disease models in mice. The earlier damages are more crucial.”

Liu says he is building a case that he hopes to present to the National Institutes of Health and other funding agencies and governing bodies to advocate for such early detection and treatment.

Until then, the Kellys and Grosecloses say they and other SKS families will continue to love and care for their precious children, raise funding and awareness, and advocate for more research.

“When I met [Liu] it was like I was meeting a rock star,” Kristen Groseclose said. “His paper changed our lives personally. [At the conference] he took an interest seeing each child personally. What he’s doing matters.”