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Celebrating the courage of families battling Rett syndrome

October 31, 2014

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Boston Rett community shares 15 reasons for hope on 15th anniversary of discovery of causative gene

A couple weeks ago, I attended an annual gathering of superheroes called “Blue Sky Girls Day.” At first glance, these people look ordinary. There wear no special capes or tights, and they summon their strongest powers for things most people take for granted. Like walking, talking, grasping objects, eating, drinking, sleeping—sometimes even breathing.

Yet many of these daily activities present epic battles for individuals with Rett Syndrome, a rare neurodevelopmental disorder that almost exclusively affects females and is caused by sporadic mutations in the X-chromosome gene MeCP2. What these individuals and their families quietly accomplish each day in real life is more impressive than the feats of any movie superhero. This is because one of the hallmarks of Rett is a striking developmental regression—in which children who seem to be developing normally all of a sudden lose the ability to speak or make purposeful hand movements—developing autism-like behavioral symptoms in addition to potentially experiencing seizures, scoliosis, breathing difficulties, gastrointestinal problems and other issues.

Stairway or opportunity for success

Blue Sky Girls Day is all about celebrating progress, from individuals with Rett syndrome making their way through the challenges of daily life to science’s climb towards a cure. (Depositphotos/billdayoneDP)

Blue Sky Girls Day celebrates the courage of families everywhere living with this disorder. Often there is a climb up a towering staircase that takes place outdoors, with firefighters, policemen, cheerleaders, and researchers uniting to support the families—both literally in their climb up the stairs, and symbolically in their rise against the challenges of the disorder.
This year’s Boston area gathering, held on the joint campus of Boston Children’s Hospital and Harvard Medical School and organized by the Rett Syndrome Association of MA, took place on Oct 11th. It was a very rainy Saturday. But of course that didn’t deter this crowd. They held the event inside, near some of the labs studying the disorder—forming a cheerleader-lined corridor festooned with glittery signs and blue balloons for the girls (and one boy) with Rett to proudly walk through.

Replica of Rosetta Stone

Rett syndrome is often viewed as a “Rosetta Stone” for understanding autism-related neurodevelopmental disorders–as it is one of the few such disorders where the underlying genetic problem is clear and there is not much debate on how to model it in mice. (Depositphotos/tepic)

This was my third year attending a Rett awareness event, and despite the gravity of the disorder, each year I learn of new reasons for hope as I interview the families, researchers and community members.

It was in 1999 that Huda Zoghbi’s team first identified MeCP2 as the gene mutated in Rett syndrome, and eight years later, in 2007, that Adrian Bird’s team made the joyous discovery that many of the core neurological symptoms are reversible in a mouse model. These two seminal discoveries have paved the way for many exciting new avenues of research—with Rett syndrome drawing the interest of top neurobiologists across the world, and being viewed as a Rosetta stone by those eager to understand autism or neurodevelopmental disorders in general.

Since this October marked the 15th anniversary of the MeCP2 discovery, I decided to assemble the reasons for hope I heard discussed at this year’s Blue Sky gathering into a “15 at 15” list for the Boston Rett community:


Basic, translational and clinical research endeavors were all discussed with excitement. Everyone in this community seems to recognize the value of science. Some examples:

(1) Ongoing Natural History Study

Over 1000 individuals with Rett syndrome across the country have contributed to an observational study that extensively documents the physical and genetic characteristics of the disorder—at a scale and level of detail that vastly surpasses previous studies. Each participant’s developmental trajectory is traced, with two visits a year until age 6 and annual visits after that. This “Natural History” study of Rett syndrome—continuing to enroll new participants and follow existing ones—began in 2006 and to date has involved four main study sites, one of which is Boston Children’s Hospital. The sheer volume of data being gathered is impressive and clearly represents an invaluable resource for the entire Rett community. Families are proud to have their daughters participate. And fortunately, just a few days ago, the National Institutes of Health announced five more years of funding through the Office of Rare Diseases Research.

Watch the YouTube video “NIH Rett Syndrome Natural History Study” explaining the significance

Visit the page for this study

Read the press release describing new funding on

(2) Treatment Trials such as the Local IGF-1 Trial

child with beautiful big blue eyes

Tracking eye gaze may be important in communicating with individuals with Rett syndrome. (Depositphotos/KatarinaGondova)

Several local families are involved in a phase II clinical trial for the treatment of Rett syndrome with a growth factor called IGF-1, led by Walter Kaufmann, director of the Rett Syndrome program at Boston Children’s. The rationale, in a nutshell, is that synapses—sites of communication between neurons—don’t mature properly in Rett syndrome, and IGF-1 may be able to help with that problem. In a mouse study published in 2009, by Mriganka Sur and Rudolf Jaenisch’s groups at MIT, a small but critical fragment of IGF-1 was found to promote synapse maturation and ameliorate some symptoms of the disorder. And fortunately, unlike certain other growth factors, IGF-1 can cross the infamous blood-brain barrier that anyone hoping to treat a brain disorder must contend with.

The phase II study for IGF-1 began last year, after completion of a phase I component that suggested the treatment was safe and well-tolerated in girls with Rett, and could potentially help with some of the breathing and behavior difficulties associated with the disorder.

Read Boston Children’s blog post on the completion of phase I

Read Dr. Kaufmann’s related comments on improving developmental disorder trials

Visit to search for Rett trials across the country

(3) Eye Gaze as a New Tool in Schools, Homes, and Potentially Doctors’ Offices

It has long been a source of heartbreak for parents that they can’t talk to their girls—finding out through spoken words or sign language what they think, feel or desire. Many are certain that their girls know what’s going on but simply can’t communicate—and have speculated that perhaps this one of the sources of their anxiety and behavioral challenges. In recent years, however, educators, parents and researchers have made progress by recognizing eye gaze as a valuable tool for communication in Rett syndrome. New methods and devices for communicating through eye gaze, both low and high tech, have come into some classrooms and homes. Additionally, there is now hope that eye tracking devices could be used in clinical settings to assess cognitive abilities, and the International Rett Syndrome Foundation has just awarded a grant to Charles A. Nelson of Harvard and Boston Children’s to investigate this idea.

Read a parent’s story on the difference eye gaze technology makes

View a presentation by Kate Ahern, Assistive Technology Specialist & Special Education Consultant

Read about the new funding awarded to the Nelson Lab

(4) Pursuit of Gene Therapy

Gene therapy is the idea of treating patients who have genetic disorders without traditional drugs or medical procedures—instead, trying to get to the root of the disorder by introducing a healthy version of a missing or dysfunctional gene, or silencing an unhealthy version. Although still in its infancy, this method has been tested in a small groups of people, for conditions ranging from inherited immune disorders, blood disorders, and hereditary blindness to cancer and Parkinson’s disease. The results have been mixed, with some serious safety concerns to be overcome–but overall successful enough to warrant significant ongoing basic and clinical research investment, for a wide and ever-growing list of disorders.

Gene therapy is a topic of great interest in Rett syndrome because the core genetic problem in this disorder is clear and relatively consistent across individuals—a loss of functioning MeCP2. In recognition of this, the Rett Syndrome Research Trust has just launched the MeCP2 Gene Therapy Consortium, which will investigate strategies for restoring proper levels of MeCP2 expression through collaborative international research.

(5) Better Understanding of How MeCP2 Works

The MeCP2 gene product is a protein that acts in the nucleus, or command center, of cells to control the activities of other genes. In order to understand how it works, scientists must investigate tons of basic questions such as what genes it controls, what makes MeCP2 itself more or less active, what other proteins it interacts with, and what controls its interaction with those proteins. Labs in the recently formed MeCP2 Consortium, as well as other groups around the world, have long been seeking answers to these questions. The lab of Michael Greenberg, chair of Neurobiology at Harvard Medical School, is a key local player whose recent work—in partnership with Adrian Bird’s team in Scotland—has revealed critical sites on the protein that control its ability to bind to a protein complex called NCoR/SMRT. Together with MeCP2 this complex acts to control the expression of many genes that play important roles in neurons. The recent research has also shown how the interaction between MeCP2 and NCoR/SMRT is modulated by the activity level of neurons. Thus these results shed light on how MeCP2 mutations in Rett syndrome might render the protein unable to respond to environmental experiences and carry out its normal duties.

Read Harvard Medical School coverage of the Greenberg lab’s 2013 publications

(6) Vision as a Potential Window on Brain Function

The Rett research team in the Hensch and Fagiolini labs at Boston Children’s Hospital and Harvard University: Takao Hensch, Alex Simon, Mari Nakamura, Annarita Patrizi, and Michela Fagiolini (shown left to right).

One of the challenges in any clinical trial for a brain disorder—particularly disorders such as Rett where communication is seriously impacted—is having an objective readout of brain function that can be consistently and repeatedly measured in patients of different ages. A basic science study from the labs of Michela Fagiolini and Takao Hensch at Harvard and Boston Children’s, published in 2012, suggests that visual processing might offer a window into cortical function in Rett syndrome. In this study, vision was thoroughly examined in Rett mice for the first time. While their eyes were fine, the mice had visual processing abnormalities in their brains that followed a pattern of developmental regression—strikingly similar to the trajectory of the well-established motor problems present in both mice and humans with the disorder.

As a result, vision is now being examined in girls with Rett syndrome participating in clinical research at Boston Children’s, through EEG recordings of visual cortex activity carried out in the lab of Charles A. Nelson. In particular, the researchers are exploring whether these vision-related brain waves might be useful as a biomarker—something that doctors could measure to tell if a new therapy is working to improve brain function or not.

Read more about vision as a potential biomarker in this Conte Center article

Read the related Boston Children’s blog post, “Visionary research on Rett syndrome”

(7) New Drug Ideas

The same mouse study that drew attention to vision in Rett syndrome also revealed that regulating the NMDA receptor (a receptor for the excitatory neurotransmitter glutamate, famous for its role in learning and memory) can help prevent the visual regression that normally occurs in mice lacking MeCP2. There are reasons to think this approach might be effective in treating circuit abnormalities beyond the visual cortex, and excitingly, several drugs known to regulate NMDA receptors. One that is already FDA-approved is ketamine. And while much caution is needed due to the known adverse effects of ketamine at high doses, the Fagiolini lab has just received funding from the International Rett Syndrome Foundation and Rett Syndrome Association of MA to begin a new study examining the safety and efficacy of low dose ketamine in treating symptoms of Rett in mice.

Read the press release announcing funding of NMDA receptor drug studies in Fagiolini lab

(8) Understanding Role of Different Types of Brain Cells

The brain is a complex mix of neurons and glial cells. Amongst neurons, there are excitatory and inhibitory varieties—neurons that promote or dampen, respectively, the electrical activity of the neurons they send signals to. While inhibitory neurons make up only 20% of the total population of neurons in the brain, they play vital roles in the brain’s development that are just beginning to be understood. In 2010 Huda Zoghbi’s team revealed that a loss of MeCP2 in inhibitory neurons alone is enough to recapitulate many of the core neurological features of Rett syndrome. Building on this, the 2012 study from the Fagiolini and Hensch labs introduced above (see #6 and #7) revealed that specific inhibitory neurons called ‘PV-cells’ are hyper-connected in Rett mice, and treatments that reverse this defect also reverse the visual regression the authors discovered. They are now working to investigate the potential contribution of PV-cell dysfunction to a variety of known Rett symptoms.

Christopher Gordon and Christopher Heller, young researchers from Beth Stevens' lab with an interest in microglial function in Rett syndrome

Christopher Gordon and Christopher Heller, young researchers from Beth Stevens’ lab with an interest in microglial function in Rett syndrome

Amongst glial cells in the brain, microglia form a population that is very poorly understood. It was only in the last decade that scientists even realized microglia play a role in brain development. Now, researchers in Beth Stevens’s lab, also at Harvard and Boston Children’s, have found that microglia play a critical role in refining neural connections—amazingly, they ‘eat’ (phagocytose) unwanted synapses—and without them a key circuit in the visual system fails to mature properly. In new efforts funded by the International Rett Syndrome Foundation, the Stevens lab is now exploring whether microglial function at synapses is disrupted in Rett mice.

(9) Increasing Knowledge of Synapse Refinement

One of the reasons it makes sense to study microglia at synaptic sites in Rett syndrome (see above, #8) is that a problem of synapse refinement in Rett has already been described. Chinfei Chen’s team, also at Harvard and Boston Children’s and a neighbor of the Stevens, Fagiolini and Hensch labs, published a study in 2011 detailing how the trajectory of synapse development differs in Rett vs. control mice for a famous synapse in the visual system. Zooming in on neural connections in the visual thalamus, where the process of synapse development in ‘normal’ mice is particularly well understood, her team showed that Rett mice initially develop connections that are very similar to controls. It’s only at a later stage of development—when the animals’ environmental experience (in this case, vision) is used to refine the synaptic connections—that an abnormality becomes evident. These findings bolstered a growing body of literature on synapse problems in Rett mice and provided a new clue as to why the disorder might manifest after a normal-looking period of development.

In a more recent study focused on the same synapse in the visual system, Chen’s lab found that synapse refinement may not always require the amount of ‘work’ (i.e. physical changes in circuit wiring) that scientists would expect. While it’s often thought that for circuits to be refined, unwanted extensions of neurons must be retracted, Chen’s group observed that even when the underlying architecture of neural connections is preserved, environmental experience can tweak circuits by simply altering the clustering patterns of synaptic sites. (Think of it like re-positioning beads on a bracelet without untying or cutting the string they’re on.) Chen believes this finding in normal lab mice is encouraging for Rett research because it suggests there may be ways to correct problems of connectivity without major rewiring of neural circuits. Her lab plans to embark on new studies to pursue this line of thinking.


While research is what propels us towards a cure, it certainly can’t happen without families and communities coming together. Some of the many heart-warming examples of teamwork I came across:

(10) Launch of “Rettland”

Katelin, age 21, with mother Melinda Lancaster, of Cape Cod, MA, supported by Katelin’s grandmother and a cheerleader for the North Middlesex Cowboys

Melinda Lancaster of Cape Cod, whose daughter Katelin, age 21, has Rett syndrome, can’t say enough good things about the way people rallied together to help Katelin get to Texas for a clinical trial which started last year. So far the trial has involved two trips, with over 40 days away from home and a cost of over $7000 not covered by insurance. Melinda collected funds through yard sales, community organizations and online donors who read her blog. “It was a real worldwide group effort to get my child to Texas,” she says. Now there is a new organization called “Rettland” that aims to consolidate fundraising efforts for families such as Katelin’s, so that they can focus on the trial without having to worry about transportation and lodging expenses.

Read Melinda’s blog

Visit the Rettland website

(11) Make a Wish Foundation Reaching Out to Rett Families

iphone upload 101414 627Kendra Malizia and Elissa Spinner, two representatives from the Make a Wish Foundation were at the Rett awareness event and announced that Make a Wish was hoping to connect with and grant the wishes of more children with Rett syndrome. The foundation offers 4 wish categories: (1) I want to have…, (2) I want to be…, (3) I want to meet…, and (4) I want to go…. The requests they receive range from simple desires for bicycles or pizza parties to big things like trips to Disney World or opportunities to meet famous athletes or entertainers.

Read a news story about San Francisco turning into Gotham city for one boy’s wish

Learn how to refer a child on the Make a Wish website

(12) Dedication of Young Cheerleaders

North Middlesex Cowboys Cheerleaders

Each year the North Middlesex Cowboys cheerleaders, led by cheer director and head coach Jill Twigg (whose daughter Olivia has Rett syndrome), come to the Boston Blue Sky Girls’ events dressed in beautiful uniforms and armed with colorful signs to cheer on the children and young adults with Rett syndrome. Each cheerleader is given the name of an individual with Rett to create a personalized poster for and make the ceremonial walk or climb with. The professionalism of these young cheerleaders, and the warmth and compassion they exude is truly impressive. I met Julia Santosuosso, a ten year old cheerleader from Hawthorne Brook Middle School in Townsend, MA. She was the cheerleader for Thomas Gallager, a boy with Rett who attends the John D. Runkle School in Brookline, MA (while it is extremely rare, Rett can affect boys). “I really like to cheer them up and make them happy,” Julia said proudly of her work with Rett families, as she and Thomas exchanged hugs.

(13) Fundraising & Fun at Strollathons


Irene and Gary Gladstone of Needham, MA with daughter Erika, who has Rett syndrome at the 2013 Cape Cod Strollathon, along with researchers from the Fagiolini and Hensch labs at Boston Children’s and Harvard

Each year the greater Boston area Rett community gathers in September for a “Strollathon” event raising funds for the International Rett Syndrome Foundation. This is part of a nationwide program which features over 30 sites and has been going on for over a decade. Families, community members, clinicians and researchers unite to walk a picturesque route through Cape Cod alongside individuals with Rett syndrome, who typically make the journey in strollers. All unite for delicious snacks, music and a raffle at the end. So far the 2014 Strollathons have raised over $700,000 nationwide—and a few have still to take place.

(14) Older Families Helping Younger Families

One of the greatest strengths of the Rett community is the way experienced moms and dads are willing to reach out to the parents of newly diagnosed children and share what they’ve learned in navigating the complex medical, educational, financial and emotional issues surrounding the disorder. For instance, when speaking about the clinical trial in Texas Katelin is participating in, her mom Melinda says, “Even if it’s not the girls my daughter’s age [21 years] that get taken care of, we—parents of girls this old—are willing to do whatever it takes so that the younger ones don’t have to go through what they did.” Irene Gladstone, whose daughter Erika, age 35, has Rett, concurs, says she feels “like a mom” for the younger parents whose young children have just been diagnosed.

(15) Collaboration All Around

Perhaps what’s most important in speeding up the climb towards a cure—our biggest reason for hope—is the level of collaboration across different constituencies in the Rett community. In addition to the partnership amongst affected families and local communities, there are unique partnerships between basic science labs, as well as bridges forming between basic and clinical researchers at special places like Boston Children’s Hospital. Not to mention the impressive level of international collaboration that goes on as doctors around the world collect and share clinical information about Rett syndrome (through efforts such as RettSearch, an international consortium of clinical researchers headed by Walter Kaufmann of Boston Children’s). Let’s hope this spirit of collaboration around Rett syndrome continues to grow, flourish and inspire researchers everywhere—whether they’re working on Rett or any other medical problem.

3 Comments leave one →
  1. melelllan permalink
    November 17, 2014 12:41 PM

    Reblogged this on Trail To A Texas Trial and commented:
    A wonderfully done, in-depth article about Rett syndrome, research, impact on families, community support and the indomitable spirit of Rett families. Done by Parizad Bilimoria. Thank you for such a wonderful, thoughtful piece.

  2. November 17, 2014 4:20 PM

    Thanks so much for sharing this with your readers, and for taking the time to share your story at the event! Hope you and Katelin are doing well

  3. Bonnie permalink
    November 20, 2014 11:12 AM

    Wonderfully written! Bravo!

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