Rett syndrome, predominantly diagnosed in females, is a neurodevelopment disorder caused by a genetic mutation on the X chromosome. Historically, it’s been rare in males and is often overlooked.
Now, researchers at the University of Colorado School of Medicine are learning more about the condition and its effects on males with new funding, a research project focused on how families of these patients navigate the diagnosis, and a plan to prepare the next generation of researchers.
“There is a growing population of families with boys who have Rett syndrome, and they are desperate for inclusion in Rett syndrome research and care,” says Talia Thompson, PhD, assistant professor of pediatrics. “They're often isolated socially, but there is community developing online.”
Timothy Benke, MD, PhD, professor of pediatric neurology, was compelled to assemble a multi-disciplinary research team after hearing the experiences of families of males with Rett.
Thompson joined Benke as co-principal investigator on this study. She is a qualitative and mixed methodologist at the Child Health Biostatistics Core with the Colorado Child Health Research Institute and ACCORDS, doing work in rare genetic conditions.
“It was a two-pronged approach, including a quantitative survey to understand the clinical characteristics and the neurodevelopmental outcomes in these boys with Rett syndrome, and also a qualitative aim to conduct in-depth interviews with families to understand how they're coming to this diagnosis and what it's like to be them,” Thompson says.
What is Rett Syndrome?
Rett syndrome affects nearly every aspect of a person’s life, including their ability to speak, walk, eat, and breathe. Symptoms can begin as early as six months old when parents begin to see their child miss development milestones or experience a regression in abilities they had already gained.
“If you can imagine the emotional devastation that goes along with watching your child lose skills and experience severe seizures and breathing problems – some of these families are in a constant state of emergency,” Thompson says.
As genetic testing becomes the standard of care when children present with seizures or developmental conditions, more male patients than previously suspected are being identified with the same genetic mutation associated with Rett.
There have been over 100 confirmed cases of Rett in males. This study includes 48 of them.
While there is no cure for Rett, the Federal Drug Administration approved a treatment in 2023 called Daybue, and there are on-going clinical trials, including gene-replacement therapy. To this point, males have been excluded from interventional clinical trials.
There are important medical and behavioral treatments, therapies, and provider considerations for these boys, many of whom present with the features as classic Rett syndrome in females. For example, proper sedation techniques, which can be harmful if done inappropriately. The lack of awareness around Rett syndrome in males can cause providers to not think about these procedures when seeing a male patient. Appropriate diagnosis can lead to patients receiving more targeted care.
Training the next generation
Benke, Thompson, and parent advocate Kate Ferdinandsen, wrote and submitted a grant to the International Rett Syndrome Foundation. The funding allowed for a two-year mixed methods study. An extension to the study was provided by Rocky Mountain Rett Association.
In addition to raising awareness and improving the diagnosis through the project, the researchers aim to train the next generation of Rett syndrome researchers. The study was designed to include three sites: the University of Colorado School of Medicine, the University of Alabama at Birmingham, and Vanderbilt University, each home to a leading Rett syndrome expert.
Jeffrey L. Neul, MD, PhD at Vanderbilt, Alan Percy, MD, from Alabama, and Benke, worked with three junior researchers to mentor and become the next generation of Rett syndrome researchers.
“It's an understudied topic, and there are not a lot of people with expertise,” Thompson says. “We want to improve the actual delivery of the diagnosis because it can be insensitive when doctors are unaware that males can be diagnosed. That can be really unsettling to a family.”
Understanding lived experience
Benke believes sharing the family’s stories is a key component of the project. Through the expertise of the research team, they can share these stories in a formalized research way.
“We want to understand how these families are receiving this diagnosis, what are some of the barriers, and how we can make it better,” Thompson says.
Dennis Gurfinkel, MPH, principal qualitative analyst in the Qualitative and Mixed Methods Research Core at ACCORDS, conducted in-depth interviews with the parents. The interviews capture the family’s lived experience of this diagnosis.
The researchers conducted 32 interviews along with gathering additional survey data from an international sample. Parents interviewed had children ranging from 7 months to 31 years old, with some alive and some deceased.
The interviews gave parents the opportunity to tell their story. Many of which had not been able to do previously. Parents were asked general questions about what it is like to have a male child with Rett. Parents often discussed a sense of isolation. Receiving a Rett diagnosis allowed them to gain services and support from online Rett groups, some specific for males.
“We heard a lot of experiences around the difficulties of dealing with the medical community, experiences of isolation, and the importance of finding community once they finally find the male Rett groups,” Gurfinkel says.
Recognition for the study
The team’s findings are also attracting accolades.
Researchers submitted an abstract of the research to the Western Medical Research Conference where they were awarded an Abbot Nutrition Subspecialty Award in the Genetics section from the Western Society for Pediatric Research.
The peer-reviewed process awards the highest scored abstract in each section. As lead author, Gurfinkel was invited to present their abstract at the conference in January.
“Many of the parents said that they were diagnosed by their geneticist, so this was the right audience to disseminate this information,” Gurfinkel says. “This research is different than the clinical scientific research that is often presented, because it focuses on the parent perspective of the diagnosis experience.”
The presentation sparked conversations about Rett syndrome in males and females, particularly around best practices. There are clinical care guidelines for females that also apply to males, but clinicians are less likely to diagnose and treat males.
Thompson says that educating this group of geneticists was very important, but the team is looking to share the information more broadly. They will present at the American College for Medical Genetics Annual Meeting in March.
