“I headed a project to plant trees in our neighborhood, joined a babysitting co-op, and watched as Kat grew,” says author Susan Zimmerman in her book Keeping Katherine, documenting the calm in her life after the birth of her first child. Born without complications or any congenital warning signs, Katherine developed quickly into a bubbly toddler and the sparkle of her mother’s eye.

“[Katherine] learned to sit up and say a few words,” recounts Zimmerman. “She played with the activity center attached to her crib, making it clang and whir like any baby would. She greeted me with outstretched arms and laughter.”

In Katherine’s baby book, Zimmerman writes about how Katherine laughed when she made funny noises at her or blew on her tummy. Katherine was delighted to sit up in the tub and play with her toys, thrilled by the splashing and the kicking. The scene had all the markings of a Hallmark moment as Zimmerman cataloged each of Katherine’s infant milestones – the first “Mamas” and “Dadas” carefully preserved in its pages.

“Several months later, I stopped writing in Katherine’s baby book,” says Zimmerman. “I told myself I was too busy. Much later, I realized the small landmarks of her progress were no longer there to be charted.”

And this is how Rett syndrome is first seen. There are no early warning signs, no sudden changes that mark one day different from the last – all the progress and developments of infancy simply begin slipping away like the tides.

Below the Surface

Rett syndrome is a genetic disorder affecting one of 10,000 girls born; afflicted infants appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. According to current research, most cases of Rett syndrome are caused by mutations in the MECP2 gene – crucial for making the protein essential for normal brain development – which is situated on the X chromosome.

“The uniqueness of this disease is that when you look at it under the microscope, the brain cells look normal – they don’t just die off,” says Aleksandra Djukic, MD, PhD, director of Rett Syndrome Center at Children’s Hospital at Montefiore Medical Center in the Bronx, New York.

“Actually, this [MECP2] gene is not necessary,” she says. “It is important for brain development, but not for early stages, which means these girls have brain cells that were born normally. In the early stages of brain development, these girls have normal brain cells, which are in the normal places. They are not damaged – they simply do not talk to each other.”


Females have two X chromosomes, so even when one has this severe defect, the defective gene is inactivated and the other chromosome is able to compensate to ensure the child’s survival. Males, on the other hand, have only one Y and one X chromosome in each cell, and because the single X chromosome cannot be inactivated, males afflicted with this disorder are subjected to the full devastating effects of the disease, and most die before birth or in early infancy.

In those patients who survive infancy, loss of speech, repetitive hand movements, breathing problems, rigid muscles, retarded growth, and even autistic-like symptoms are common by the age of 4. It is these similarities with autism that may cause the most damage, perpetuating a fairly common misdiagnosis among physicians, where both patient and parents are left hovering in a limbo between developmental disorders, such as cerebral palsy, autism, and even Angelman syndrome.

Like many therapists working with exceedingly rare disorders, DeLana Honaker, PhD, OTR, BCP, associate professor of the occupational therapy program at Pennsylvania-based Elizabethtown College, has only had a few patients with Rett syndrome. However, the patients she has worked with have impressed upon her the futility of early diagnosis for Rett syndrome.

“You look at the symptoms for autism spectrum disorder and the child won’t demonstrate all of those symptoms, but maybe a few, such as lack of eye contact and social skills, as well delayed fine motor, gross motor, and communication skills,” says Honaker. “But it’s not classic – it doesn’t have all the symptoms. You look for symptoms for cerebral palsy and again the child won’t demonstrate all of the symptoms for that. Or seizure disorder – again, the child won’t demonstrate all of the criteria. It really comes down to the fact that diagnosis for Rett syndrome was made by determining everything that it wasn’t.”

Fighting a Losing Battle

While currently, Rett syndrome falls under the grouping of “pervasive developmental disorders”, some healthcare professionals argue that Rett syndrome is misclassified as a pervasive developmental disorder, in a similar fashion to such disorders as fragile X syndrome, tuberous sclerosis, or Down syndrome where observers can see autistic features.

“Once a child is diagnosed with autism, there are delays, but there aren’t any further regressions,” says Honaker. “For the most part, as with most diagnoses under the autism spectrum umbrella, there won’t be any further regressions, so therapists can continue and build up in rehabilitation. We may only make incremental progress for some children, or phenomenal progress for others, but this remains one of the distinguishing features between Rett syndrome and autism – Rett just continues to deteriorate.”

Typically, the limited motor control seen in patients with Rett syndrome – especially those who have developed scoliosis – can be maintained with rigorous physical therapy, as well as braces or casts. In some cases, physical therapy can also help sustain walking skills, balance, and flexibility, while occupational therapy may improve purposeful use of the hands.

“I have used special equipment, such as splints, to modify the hand movements for these patients,” says Honaker. “With one girl, we did use some hand splints in order to give her a more functional grasp with adaptive equipment to feed herself. At age 6 or 7, we could still do semi-motor activities with her in the classroom, and she could play with hand manipulatives and toys and that kind of thing.”

She continues, “[However,] eight years later, when she was getting ready to graduate from the school system, there was nothing. She had a lot of contractures that had developed within the hand and within the wrist. She had almost total flexion of everything in the hands and the wrist. It was extremely difficult, despite that over the years we had been continuously doing range-of-motion flexing exercises with her. While we did do some splints when she was younger, as the condition progresses and skills regress, there really isn’t a whole lot that you can do with splints and that kind of equipment.”

Another stereotypical symptom of Rett syndrome is the progression of repetitive hand movements, which includes hand-washing, hand-wringing, hand-clasping, and hand-mouthing – compulsions that can be almost constant while the patient is awake. Therapists use a wide variety of techniques to redirect this particular impulse control, or at least draw the patient’s attention to their impulses, which may help in reducing their frequency. 

“Sometimes we use manipulatives, or other things that they can be doing with their hands, so they’re using their hands for something else; it’s something we can start to build on once they start to understand that concept,” says Nicole Boucher, MT-BC, NMT, board certified neurological music therapist and founder of Wakefield, R.I.-based Hands in Harmony, LLC.

“One of my clients was very contracted, so just her learning how to open up her hand and play an instrument with a flat palm, instead of in a closed fist, was a starting point. From there, she would learn that once she would bring her hands together, I would stop the music. In order to start the music again, she’d have to stop wringing. Honestly, in my experience before, I didn’t think it was possible to control the hand-wringing, but I have an instance now where one of my clients has learned to control her wringing, to an extent.”

Gasping for a Cure

One of the most upsetting and difficult symptoms for the parents of Rett syndrome is the irregular breathing patterns. Breathing rhythm for Rett syndrome patients can alter erratically from minute to minute, most people having several different rhythms and switching between them. This can result in behaviors such as hyperventilation or breath-holding, but sighing seems to be the most common response.

According to Djukic, “Rett patients have severe problems with autonomic dysfunction, which includes breathing, which includes peripheral circulation and heart functioning, and also gastrointestinal functioning. These patients have problems sleeping, and often suffer severe anxiety, as well as problems with bone development, so their bones are weak, and they frequently develop scoliosis.”

Nutrition is also a problem for this patient demographic, as most children with Rett syndrome have trouble eating, and therefore are often shorter and weigh less than other children their age. Due to the inconsistency of their diets, constipation can also be a severe and chronic problem. While some children with Rett syndrome may respond to a high-fat, high-calorie diet, the obstacle of swallowing these foods persists.

“Their muscles are not weak, and individually they can work correctly,” says Djukic. “However, they don’t work as a group, and you need many muscles – lips, cheeks, tongue – and breathing to be coordinated in a very sophisticated fashion in order to swallow. So these kids frequently have problems feeding and many of them need to be fed by a tube.”

Without an active ability to speak, one of the challenges therapists continue to see in working with this demographic is the appropriate bridge of communication effective in reaching these patients “locked in” by this disease.

“In the clients that I’ve had, it can be frustrating, because a lot of times, the lack of communication and with the motor skills, it’s difficult to find a form of communication that’s effective for them,” says Boucher. “So if they can’t speak, and using their hands is difficult, then signing is not necessarily an option. Communication can be a big struggle, depending on the progression and severity of the patient’s condition.”

Hope on the Horizon

Despite the overwhelming obstacles that Rett syndrome patients undergo on a daily basis, hope remains – and not just from the patients and therapists interacting with these stalwart survivors. Recently, researchers in a paper published in Nature Neuroscience demonstrated that MECP2-deficient astrocytes stunt the growth of neighboring neurons. Even more remarkable is that these neurons can recover when exposed to normal glia in culture.

Glial cells comprise nearly 90 percent of cells in the brain, acting as a support network for neurons, whether providing the structural underpinnings and guidance of the neuronal processes that carry information, or creating protective insulation for axons – essential to the health of neurons.

The researchers found that MECP2-deficient astrocytes could not sustain normal neuronal growth, as demonstrated by the reversal of development in Rett syndrome patients. Moreover, the research suggest that MECP2-deficient astrocytes secrete a toxic factor that impacts the entire neighborhood of neurons, including neurons with normal MECP2.

Recent studies from other groups, including Tom Maniatis, PhD, a neurodegenerative disease researcher at Harvard University in Cambridge, Mass., have implicated glia in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder that leads to the death of motor neurons and total paralysis.

“In Rett Syndrome, faulty glia seem to poison neurons, inhibiting growth; in ALS glia appear to release a toxic factor that kills motor neurons,” says Maniatis, highlighting that “studies of the role of glia in a broad spectrum of neuronal diseases should lead to exciting advances in understanding disease mechanisms.”

As the scientific community explores the therapeutic implications of this new research, therapists and caretakers continue to push toward innovative and collaborative techniques that might preserve the dwindling skills of this patient demographic – and bring them one more day, one more step, closer to a cure.

— Bob Stott is editor of Therapy Times. Questions and comments can be directed to editorial@therapytimes.com.