Gene testing conducted at Cincinnati Children’s confirmed that Jack had the SKS mutation, which also led to a treatment attempt.
Research over the years, led in large part by Krueger, had revealed that TSC also is driven by dysfunctions in the mTOR pathway. Krueger and colleagues demonstrated that several manifestations of TSC, including brain tumors and seizures, could be controlled through the mTOR inhibitors sirolimus and everolimus.
Suspecting they were facing a new “mTORopathy,” the doctors at Cincinnati Children’s placed Jack on a daily dose of sirolimus.
Enter Circadian Medicine
At first the treatment worked well. Some of Jack’s behavioral issues improved dramatically. However, he also turned into a “night owl,” a disruptive sleep pattern that was causing a new set of issues.
Jack’s new problems happened to occur in the right place.
It turns out that while some scientists were studying how mTOR dysfunction affects brain development, another set of scientists were learning that mTOR also serves as one of the core genes regulating the body’s circadian clock.
At Cincinnati Children’s, John Hogenesch, PhD, and David Smith, MD, PhD, have been leaders in studying how medication effectiveness can be affected by circadian rhythms, and how medications can affect the body’s clockworks. They soon concluded that Jack’s sleeping problems were caused by receiving too much of the sirolimus. This in turn opened a new page for families looking for ways to manage symptoms.
At the gathering in October, experts at Cincinnati Children’s walked families through a series of tips and techniques for measuring and managing sleep disorders. For children with SKS they say sleep may serve as both a potential biomarker for monitoring the condition as well as a form of treatment.
“We do believe that achieving healthy sleep could ameliorate a number of symptoms for children with SKS,” David Smith says.
Looking ahead
In August 2019, the Grosecloses and other families launched the Smith-Kingsmore Foundation to continue raising awareness about the condition and to raise funds for more research.
More work is needed to prepare for potential clinical trials of proposed SKS treatments, investigators say. Designing a meaningful clinical trial for a very rare condition that also has a complex web of symptoms will be no easy task, Krueger says.
However, the effort is worth it, for children with SKS and beyond. Krueger says what scientists learn about SKS, combined with knowledge gleaned about TSC, could lead to deeper understanding and better management of other more-common conditions such as seizures and autism spectrum disorders.
Mike Groseclose says the event held at Cincinnati Children’s was just the beginning.
“We want to blaze a trail here. We know that SKS is underdiagnosed, but we don’t know if there are another 1,000 people or 100,000 people,” Groseclose says. “It was awesome to learn more about the progress made so far. Even though it’s in its infancy, the science is much further along than we understood. It was great for everybody to hear that.”
—Article written by Tim Bonfield