Mount Sinai’s Seaver Autism Center for Research and Treatment Gives Hope to Children with Rare Genetic Disorders

When Rowland Egerton-Warburton was born in 2012, he was given a clean bill of health by doctors. However, when he returned home, his parents, Genie and Jamie, noticed that Rowland had some unusual physical and behavioral traits that they hadn’t observed with their other children: he had a notched eyelid, clenched fists, and an unusual gaze toward lights and moving objects. As the months passed, he would meet developmental milestones—such as cooing, pulling himself up, and crawling—only to have progress stop.

During her pregnancy, Genie had undergone a chromosomal microarray analysis (CMA), a genetic test that can identify abnormalities in DNA, but her results did not flag anything unusual. She and Jamie spent the next four years trying to figure out what was happening to their son, without receiving any conclusive answers from medical professionals.

In August 2016, when Rowland was four years old, Genie and Jamie decided to have a whole exome sequencing test, involving saliva and blood tests for themselves and Rowland.. Whole exome sequencing is a more advanced genetic test used to identify variants in DNA that may relate to specific and rare conditions. This time, Rowland was diagnosed with ADNP syndrome, a rare genetic condition that is non inherited—meaning it is not passed from a parent to a child. ADNP syndrome causes a range of developmental issues and can lead to autism spectrum disorder (ASD).

The diagnosis was a shock, but finally provided some clear answers on what was causing Rowland’s developmental and behavioral issues. The diagnosis also provided the opportunity to seek further help and investigate possible treatments for his symptoms.

“Opens up your world”

“If you actually know that your child has a specific syndrome, it helps doctors understand what your child is going through,” Genie says. “As a parent, you're able to say to your pediatrician or to your neurologist that you know these facts about ADNP syndrome and to ask, ‘How can we help our child meet these milestones? How can we better serve our child?’ It also opens up your world to reaching out to Facebook groups and ways to connect with parents who deal with similar issues with their children.”

Rowland’s diagnosis led Genie and Jamie to bring ADNP syndrome to the attention of the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai. They met with Joseph D. Buxbaum, PhD, Professor of Psychiatry, Genetics and Genomic Sciences, and Neuroscience, and Director of the Seaver Autism Center, and Alexander Kolevzon, MD, Professor of Psychiatry and Pediatrics, and Clinical Director of the Center. Genie and Jamie later joined the Seaver Autism Center Associates Board and have been active members ever since.

Dr. Buxbaum is co-founder of the Autism Sequencing Consortium (ASC), an international group of scientists who share autism samples and data. Dr. Kolevzon’s research focuses on understanding the neurobiology of autism and related neurodevelopmental disorders, with an emphasis on studying specific genetic forms of autism and developing new treatments.

In the spring 2017, Rowland underwent a comprehensive evaluation, including neuropsychological testing, by Dr. Kolevzon and Paige Siper, PhD, Associate Professor of Psychiatry at Icahn Mount Sinai and Chief Psychologist at the Seaver Autism Center.

“Broadly speaking, our assessment was to evaluate his level of cognition and adaptive behavior, including things like communication skills, socialization skills, and motor skills,” Dr. Kolevzon says. “We diagnosed Rowland with autism spectrum disorder and intellectual disability.”

An array of services

Being able to provide a diagnosis of autism entitles a child to a whole array of services that may otherwise be challenging to access, including behavioral therapy, speech therapy, occupational therapy, and physical therapy.
Drs. Kolevzon and Siper were also able to recommend what types of therapies would help Rowland specifically.

“The biggest thing was helping him get access to the services he needed,” Dr. Siper says. “For instance, getting 40 hours a week of applied behavior analysis, or ABA therapy, which is an evidence-based behavioral treatment for autism where they work on communication and social skills, among other areas.”

“We make recommendations about what the most appropriate classroom setting is for him and suggest specific strategies based on his developmental age and level of functioning,” Dr. Kolevzon adds. “We also make recommendations about physical health monitoring, and consider medications to manage symptoms.”

Genie has since been able to coordinate a team of specialists in her school district to work with Rowland, and reached out to Dr. Siper to provide additional guidance to the team about the specifics of his rare condition.

“Dr. Paige Siper has been incredible,” Genie says. “When I felt Rowland’s team wasn't able to work with him effectively given some of his maladaptive behaviors, Dr. Siper joined a Zoom team meeting with his BCBA (board certified behavior analyst), his SLP (speech language pathologist), occupational therapist, and physical therapist. She was not only able to really explain the syndrome, but also explain how sensory-seeking Rowland is, and why he constantly has to have something in his mouth. That's a common characteristic of ADNP syndrome. It was incredibly helpful for all of his providers to have her explain to them how to work with him.”

Genie and Sandra Bedrosian Sermone, founder of the ADNP Kids Research Foundation, became interested in creating a research program at the Seaver Autism Center to conduct multidisciplinary research and to involve other families with children with ADNP syndrome. The foundation was able to facilitate funding for the program, which was set up in 2018.

“In 2020, we published the results of a study looking at the clinical characteristics of ADNP and the relationship to gene expression changes, followed by another study in 2021 looking specifically at sensory symptoms as a core feature,” Dr. Kolevzon says.

Advancing research

The discovery that ketamine could potentially be used in the treatment of ADNP brought a new point of focus for the Seaver Autism Center’s research. The ADNP gene affects brain formation, development, and function. Individuals with ADNP syndrome produce roughly half of the proper amount of protein usually produced by the gene. Based on research carried out in 2019 at the University of Alabama using machine learning, ketamine was shown to potentially increase ADNP protein production. Further studies using mouse models and preclinical techniques suggested that a low dose of ketamine was protective against neurotoxicity, meaning that low doses could be used safely in clinical trials.

“We used those findings to form the basis of a clinical trial. Ketamine, based on several lines of converging evidence, has been shown to promote synaptic plasticity and potentially enhance learning and memory,” Dr. Kolevzon says. “So we decided to do this study, and the ADNP Kids Research Foundation, spearheaded by Sandra and Genie, funded it. We administered a single dose of intravenous ketamine to 10 children with ADNP syndrome and followed them for one month after the infusion. We published the results in 2022 as a proof of concept that ketamine was well tolerated and associated with improvement in a variety of clinical symptoms.”

“However, it’s important to note that this was only a single dose study without a placebo control, so bias has to be factored in with the results,” he says. In addition, the improvements made by some participants were not long-lasting. However, there was enough evidence of ketamine’s potential use for the treatment of ADNP syndrome for the Seaver Autism Center team to pursue funding for future trials of the drug.

“We have a full trial protocol developed, and we have approval from the Food and Drug Administration to start the research study,” Dr. Kolevzon says. “We have applied to the National Institutes of Health for a grant to start a trial. That grant was reviewed very well, but not funded yet, so we are still looking for opportunities for funding.”

Meanwhile, the research team at the Seaver Autism Center is working on a number of other studies into ADNP syndrome. Dr. Buxbaum is currently developing a mouse model to test different therapeutics. Michael S. Breen, PhD, Assistant Professor of Genetics and Genomic Sciences is studying blood samples to see whether the expression  of certain genes are upregulated or  downregulated—increased or decreased —in response to ketamine.

“We are still very invested in ADNP syndrome and think it's a really important gene,” Dr. Kolevzon says. “We know it's critical for proper brain development and potentially provides a window into understanding autism more broadly. What's unique about the Seaver Autism Center is that we are able to do everything from molecular studies, to animal modeling, to clinical trials.”

ADNP syndrome is one of a number of rare, genetic syndromes that the center is currently investigating. Others include Phelan-McDermid syndrome, FOXP1 syndrome, and DDX3X syndrome. Clinical research is typically conducted across three different phases: clinical characterization of the syndrome, natural history (how the clinical picture changes over time) and clinical trials of potential therapeutics.

The Phelan-McDermid syndrome program is at the most advanced stage of research, with 10 years of natural history study and several clinical trials already completed. The research is now moving on to investigations with a specific gene therapy.

“I think each one of these specific genetic forms of autism provides opportunities to develop treatments in autism more broadly,” Dr. Kolevzon says. “According to the Centers for Disease Control and Prevention, in the United States, one out of 36 kids has autism, and 1 percent to 2 percent of them have autism because of Phelan-McDermid syndrome. If we can use what we learn about Phelan-McDermid syndrome to develop a treatment for even 10 percent of people with autism with no known genetic cause, that would be game-changing.”