Reaching beyond Rett Syndrome: How a family and the Waisman Center are working to improve care for those with rare syndrome

By Emily Leclerc | Waisman Science Writer

The Koenig Family
The Koenig Family, Ella is in orange

Eleanor (Ella) Koenig is a bright and bubbly two-year-old. She loves going outside and spending time with her family. Going on walks is a particular joy of hers. “They’re one of Ella’s favorite things,” says her mother, Jennifer Koenig, Ella has this huge beautiful smile and an infectious laugh. At first glance, she seems like any other bouncy toddler, but Ella’s journey is very different. She is unable to walk or crawl and is non-verbal. She is unable to sit independently. The road to a diagnosis has been a rollercoaster for her and her family that finally led to the answer: Rett syndrome.

Rett syndrome is a rare genetic neurodevelopmental condition that affects nearly all parts of a person’s life. The syndrome occurs predominantly in girls (male diagnoses are being increasingly recognized) with approximately 1 in every 10,000-15,000 girls born receiving a Rett diagnosis. Individuals with Rett syndrome typically have impaired speech, mobility, motor control, and breathing and these will often deteriorate over a person’s lifetime. Seizures are also a common symptom that many individuals endure. A key marker of Rett is near constant repetitive hand motions. Ella experiences many of these telltale challenges.

“When she was around four-to-six months, I started noticing that something was off,” Jennifer says. “She wasn’t sitting on her own or meeting milestones like her older brother was at this age,” Another hallmark of Rett syndrome is a regression 6-18 months after birth. Children start to lose skills or abilities that they had gained. At Ella’s six-month check-up, Jennifer and her husband Adam brought up their concerns.

After months of being told she would catch up, Jennifer and Adam pushed to see a specialist. Ella was referred to a physical therapist. But the therapist quickly told Jennifer and Adam that Ella needed to see a neurologist. “That’s when we realized that this is serious. She’s not just behind,” Jennifer says.

Several months after Ella’s first birthday, she received her diagnosis of Rett syndrome. “It was devastating, life changing. It’s rare – we hadn’t heard of it before we started this journey and it’s a very difficult diagnosis to process,” Jennifer says. Ella’s neurologist recommended that the Koenig family receive care at the Waisman Center Clinics. While Waisman does not have a Rett-specific clinic, several of the center’s specialty clinics see individuals with Rett syndrome including the Autism and Developmental Disabilities Clinic, the Neuromotor Clinic, and the Communication Aids and Systems Clinic. Ella and her family’s first encounter with the Waisman Center was through the Neuromotor Clinic.

Clinical care for every step of the way

The Neuromotor Clinic is an interdisciplinary clinic with a broad range of clinicians to provide care and consultation to individuals with disabilities that have neurological and motor disability or a condition that affects motor development. “We see patients that require a lot of multidisciplinary care and girls with Rett syndrome fall into that category,” says Janet Legare, MD, pediatrician and Neuromotor Clinic director. The clinic includes a physical therapist, occupational therapist, speech-language pathologist, audiologist, social worker, and a nurse practitioner in palliative care who all work together with Legare to provide well-rounded comprehensive care.

“One thing about the clinic that we pride ourselves in is that we look at every patient as a full person,” Legare says. “It is really helpful to have people at the top of their field in the clinic who are able to tell you different aspects of a diagnosis and how it all comes together to make a person unique.”

The clinic team works together to provide their patients with the best quality of life possible. For individuals with Rett syndrome that can involve a variety of things. “We look at muscle tone. How is their muscle coordination? How is their mobility? How is their fine motor control? Can they do things like daily living activities at home? How are their interactions with peers and family? What is their communication ability? How are their moods?” Legare says.

They review eating, sleep, screenings for medical conditions associated with the diagnosis, walking, wheelchair use, communication needs, and so much more. “It’s nice to reground when we talk to the specialists in each area because it can help us as caregivers refocus on what we need to be doing to best help Ella out,” Adam, Ella’s dad, says. “I view these appointments at the Waisman Center as the best opportunity to make bigger decisions about her care.” Ella visits the clinic every six months.

The Koenig’s are very grateful for the care they receive at Waisman and for the support the clinic provides. Legare and the clinic team work hard to provide opportunities for their families to meet and create space to support one another. With families’ permission, the clinic has specific dates when it schedules families with similar diagnoses to come in on the same day so that they can meet and talk with one another.

Janet M. Legare, MD
Janet M. Legare, MD

With rare conditions like Rett syndrome, it is very easy for families to feel isolated and alone. Legare and the clinic team felt that bringing families together was a way to show that there are others who understand the journey and the challenges. That can be incredibly comforting. “They really benefit from talking to each other. One family really benefitted from seeing the older girls and how different families have coped with things and obtained social supports,” Legare says.

For Jennifer, Adam, Legare, and the clinic team, their primary goal is to ensure that Ella is as happy and healthy as possible. A big step forward has been the Food and Drug Administration’s (FDA) recent approval of the first drug treatment for Rett syndrome.

Before this drug, trofinetide, there were no treatments for Rett syndrome. Ella recently started on this medication. While trofinetide is a major breakthrough, it is not a cure for Rett. “The new medication may help some of the symptoms but it is not a total game changer,” Legare says.

Another huge step forward has been helping Ella get a communication device. The Neuromotor Clinic will often refer patients to Waisman’s Communications Aids and Systems Clinic (CASC). CASC helped Ella get set up with her communication device, which is called a Tobii. It allows her to more easily communicate with her family and those around her. She uses her eyes to look at a picture on the screen and the device speaks for her. Initially Jennifer and Adam were helping show Ella how to navigate the device but now Ella can navigate circles around them. “You can choose different voices for the Tobii and the one that she uses is called ‘Ella’, which is the little girl voice. It was kind of meant to be,” Jennifer says. “Being able to hear her say mom, dad, I love you or simply just thirsty is pretty amazing.”

Being able to communicate has unlocked more of Ella’s personality and given her another important outlet for expression. The device has also made it much easier for Ella to showcase just how intelligent, intuitive, and in tune with her emotions she is.

The Koenigs appreciate being a part of the Waisman Center and the clinics not only for the excellent care that Ella receives but also because they want to contribute to the research being done on Rett syndrome. “There’s a lot going on with Rett syndrome right now as far as research, medications, and gene therapy,” Jennifer says. “There may not be a cure in Ella’s lifetime but if through these appointments, we can help doctors find a cure for the next generation of girls, it’s amazing to be a part of that.”

Working in the lab to help everyone with Rett syndrome

Qiang Chang, PhD
Qiang Chang, PhD in his lab at the Waisman Center

In another part of the Waisman Center, there is a dedicated investigator who is working to better the future of every girl with Rett syndrome through his research. Qiang Chang, PhD, director of the Waisman Center, Waisman investigator, and professor of medical genetics and neurology, has been researching Rett syndrome for more than two decades and has contributed important work to the field.

Chang has been involved in Rett syndrome research since the very beginning of the field. In 1999. the genetic cause of Rett syndrome, mutations in the gene MECP2, were discovered by a team led by Huda Zoghbi, MD, Baylor College of Medicine in Houston, Texas. Not long after that discovery was published, Chang joined the lab of Rudolf Jaenisch, MD, founding member of the Whitehead Institute for Biomedical Research and a professor of biology at the Massachusetts Institute of Technology (MIT)as a postdoctoral fellow. Jaenisch is a world-renowned expert in mouse genetics and creating mouse models. Just as Chang joined his lab, Jaenisch’s lab was working on creating a mouse model of Rett syndrome.

“The postdoc who was working on the model had just left the lab so I took over the project when I joined,” Chang says. “This was at the very beginning of basic research in the field because identification of the gene opened the door to model the disease. The mouse model created, at the time, was the most powerful tool to study the disease and I joined the field right at that time.” In 2001 Jaenisch’s lab published their Rett syndrome mouse model.

From there, Chang’s career in Rett syndrome research bloomed. “I continued that line of work because it was the beginning of the field. It’s rare that you have the opportunity to join at the start so there was a lot of new knowledge to be gained,” Chang says.

Chang’s postdoctoral work actually helped lay the foundation for the new drug trofinetide that was approved this year. The researcher whose work would lead to trofinetide, Mriganka Sur, PhD, Newton Professor of Neuroscience and director of the Simons Center for the Social Brain at MIT, was inspired to investigate the role of growth factors in Rett syndrome after reading some of Chang’s later postdoctoral work on the role of brain-derived neurotrophic factor (BDNF) in Rett syndrome disease progression.

Then in 2007, Chang joined the Waisman Center where he would build his own lab dedicated to studying Rett syndrome and understanding how mutations in the MECP2 gene lead to the condition. The gene MECP2 makes the protein MECP2. This protein is important throughout the whole body and interacts with a large portion of the genome. “This is a protein that binds to 1/3 of the genome. It’s essentially binding everywhere. There are many genes that are dysregulated when its function is disrupted because of the mutations found in Rett syndrome. But the changes are all quite modest,” Chang says. “There are many small changes in expression which makes it hard to understand the mechanisms behind Rett because it really is a lot of little things adding up together.”

His work over the years has led to several important insights into the specifics of MECP2’s function and how mutations in the protein lead to symptoms common in Rett syndrome. Today, Chang continues his research while serving as the director of the Waisman Center, with more specific goals of studying the disease in models to find new drug targets and delving deeper into the function of MECP2 and its impact on the development and function of the nervous system.

He wants to fill in all of the steps in the middle. We know the cause of Rett syndrome. We know the symptoms the condition presents with. What is not known is what happens in the middle. How does mutations in MECP2 cause Rett syndrome? This question is the main one Chang’s research is focused on. “There are many questions left we need to answer,” Chang says. His overall hope is that his research will contribute to more effective treatments and hopefully one day a cure.

The Koenigs take comfort in the research that goes on at Waisman and all across the country. Even though a cure may not be a part of their journey, the hope of better treatments is important. “I am a science teacher so I’ve always been interested in genetic therapies and gene editing and similar things,” Adam says. “Then it took on a more personal flair with Ella. It’s easier to stay optimistic when I look at some of the research and trials and things that are going on. You want to have the hope that it can get better and it helps keep me going day to day.”

For now, the Koenigs will keep on making the best of each day and will continue to get Ella every support and service that she needs while absolutely doting on her and her siblings. “Eleanor is not defined by her diagnosis,” Jennifer says. “She is a beautiful, patient little girl who also happens to have Rett syndrome. Every day with her is a gift.”