Why Rett syndrome is an important disorder
Rett syndrome is an important disorder to a great many people. This is not so much because it affects several thousand individuals worldwide (it is a rare disease), or that it results in substantial disability but because the recognition of its complexity has paralleled fundamental developments in pediatric neurology, neurogenetics, and neurodisability. It has become impossible to make sense of any neurodevelopmental disorder without a thorough multi-dimensional perspective.
The characterisation of Rett syndrome
The characterisation of Rett syndrome originated in self-confident, clinical observation: Andreas Rett observed facts (i.e. empirical data) and in the face of incomplete knowledge, made a situational judgement that the girls he had observed who showed stereotypical hand movements and other signs shared a specific syndrome that had not been described previously. This approach remains at the core of all good medical practice.
Gaining wide recognition in the medical world
Bengt Hagberg broached the subject of an unusual disorder he had been observing since the late 1950’s and early 1960’s throughout Sweden. Unlike Andy Rett, he did not write about these findings, simply collecting the clinical data. He was aware of Andy Rett’s work, but was at first skeptical of a connection as he had not identified hyperammonemia in his patients in contradistinction to Andy. When he found out that this finding was in question, he presented his collected data at a meeting of European child neurologists in the late 1970’s and was joined subsequently by Jean Aicardi, in preparing a manuscript for publication. Subsequently, a chance meeting with Andy led Bengt to term the disorder Rett syndrome and with this single publication in the Annals of Neurology in 1983, a literal explosion of reports emerged from throughout the world heralding this heretofore unknown and unrecognized disorder.
Bengt then encouraged a number of important efforts to standardize consensus diagnostic criteria, provide initial staging criteria, and recognize variant features that are well-engrained today.
“In 1960 as an Associate Professor in child neurology in Uppsala, Sweden, I met an 18-month-old girl with a deviating development I had never seen before. From having been quite normal, she had developed an autism-like condition with ataxia, loss of hand function, and the appearance of stereotypic hand wringing. Her father insisted that all efforts should be made to discover the cause of the disease. Everything was shown to be completely typical, even the findings of a brain biopsy from the frontal lobe. By 1980, I had met another 15 girls with the same peculiar, and for me unknown, disorder.
In 1981, I was invited to a congress in Toronto to lecture on known causes of intellectual disability. As I spoke about the ‘hand-wringing’ syndrome, a loud voice from the back of the room was heard. Dr Andreas Rett, who was attending the congress, ran down the aisle toward me, excitingly saying ‘Ich bin Rett’ (I am Rett). In 1966, Dr Andreas Rett had observed two preschool-aged girls who sat next to each other in his waiting room, both making the same peculiar hand-washing movements. He recalled having seen other similar patients over the years and made a film of four girls and brought it to medical meetings all over Europe, asking if the syndrome had been seen elsewhere.
In 1983, our paper (Hagberg et al. 1983) appeared in the Annals of Neurology as the first English paper on the syndrome, and the syndrome became recognized worldwide.”
Rett syndrome’s biological basis
Andy and Bengt started a movement that has created a groundswell in clinical and laboratory investigations leading to the present state of knowledge and underscoring the importance of discovery and perseverance in tracking down the causal factor of the syndrome, understanding its natural history, and stimulation of translational studies. The phenotype of Rett syndrome was refined to suggest diagnostic criteria, update them based on better observation, and pave the way to the discovery of its biological basis.
In 1999, there came the important breakthrough in genetics with mutations found in the X-linked MECP2 gene, with crucial implications for diagnosis and new questions on pathophysiology, many of them still unanswered. Thus, Rett syndrome became the first neurodevelopmental disorder related to defective transcription of methylated DNA.
Importantly, clinicians recognised the value of behavioural manifestations by characterising the association of the cognitive, language, social skills, and motor control features that constitute the behavioural phenotype of Rett syndrome. The behavioural phenotype of conditions that were described around the time of Andreas Rett’s first observa- tions (e.g. Williams syndrome , Lesch–Nyhan syndrome , or Angelman syndrome ), remain highly relevant to current clinical practice, in particular with regard to diagnosis, management, and outcome measures.
The clinical course of Rett syndrome
The clinical course of Rett syndrome poses a challenge to the classic distinction between neurodevelopmental disorders, in which a brain defects cause symptoms from birth, and neurodegenerative disorders in which progressive, life-limiting changes induce the gradual loss of acquired skills. In Rett syndrome, most infants do not show any obvious developmental problems. After a few months, however, severe regression occurs, together with a delay in acquiring new skills, emergence of autistic features, loss of purposeful manipulation skills replaced by stereotyped hand movements, ataxia and apraxia, while no neuronal degeneration explains the change. This has led clinicians to consider development and neurodevelopmental disorders in a more complex way than the linear approach that has long prevailed in the field.
A mother’s journey
“When I started on the Rett journey more than 35 years ago, I was simply the mother of a precious baby girl, Stacie. She had developed as typically as her two older brothers until at 18 months she had become withdrawn and irritable. When she began to lose skills without explanation, there was no place to turn, not even in the medical community. She was described as ‘one of a kind’ and a ‘medical enigma’. There was no one to help, and there were no answers for the myriad of questions about what had gone wrong, and why. A lonely, frustrating decade ensued, with visits to several specialists who said with regret that we would probably never have answers. One doctor even dared to suggest that her autistic-like behavior and regression must be my fault, due to an outdated Bruno Bettelheim ‘refrigerator mother’ theory. From that day forward, I referred to the day of diagnosis as D-Day.
By the time Stacie was 9 years old in the spring of 1983, she had a diagnosis of severe-to-profound intellectual disability. She was ambulatory but nonverbal and she cried a lot for unknown reasons. Her hands were in continual motion, which seemed an insignificant factor considering the totality of her disabilities. She had lost the ability to use her hands and needed help for every aspect of daily living. Yet, she was as beautiful as a porcelain doll and her eyes were bright and searching. We had begun to believe the prediction that we would never know what had gone wrong, when out of the blue, we received a call from Dr Mary Coleman at the Children’s Brain Research Clinic in Washington, DC. Dr Coleman had been following Stacie since she was 2 years old, ruling out the most common neurological disorders, and even testing her for the rarest of syndromes, always passionately committed to finding a diagnosis. Attending Grand Rounds at a pediatric hospital in France, she had listened acutely as Dr Jean Aicardi presented a paper on newly discovered disorder, Rett syndrome, about to be published in the Annals of Neurology. Dr Coleman described it as a ‘eureka moment’ as she instantly recognized all of Stacie’s symptoms. We anxiously awaited the publication of the first English-language paper several months later, and when it arrived, we read it in near disbelief at the likeness of photographs and the precise description of our child’s deviation in development. We rejoiced in odd celebration for finally, a diagnosis. And while the devastating diagnosis brought more questions than answers, it was at last a comfort to know that Stacie was not ‘one of a kind’ and that we were no longer alone. Stacie had been, all at the same time, my deepest despair and the height of my greatest joy. Her courage and her sweet spirit inspired me to reach out to others and try to make a difference.
I founded the International Rett Syndrome Association (IRSA) in early 1984 as an organization dedicated to our slogan to ‘Care Today … Cure Tomorrow’. IRSA was The Club You Never Wanted to Join, a fraternity of parents who were united in pain and anguish, denial, anger, despair, frustration, bewilderment, and fear. It was created as a place where a confused parent could reach out for immediate answers and resources that increase their knowledge and show them how to lessen the physical challenges and minimize the emotional burdens that come with having a child with special needs. Our first family conference took place in conjunction with the 1985 International Symposium and 35 families from the USA and Canada traveled to Baltimore to meet Dr Andreas Rett and the conference sponsor, Dr Hugo Moser. As families gathered at the hotel that first night, we were completely awed as one by one, girls were wheeled in the door demonstrating the same hallmark hand-wringing movements that before had seemed trivial. The bond which parents felt was magical and healing; just to know that we had each other and some kind of hope for answers. We quickly formed a shared commitment to work together to make better lives for our beloved daughters. Without really recognizing it, we were following the sage advice of St Francis of Assisi: ‘Start by doing what is necessary, then do what is possible, and suddenly you are doing the impossible.’
At that historic meeting in Baltimore, not all of the medical community accepted Rett syndrome as a distinct clinical entity. It would take some years of persistence, medical and public awareness campaigns, and the information and data provided by the National Institutes of Health (NIH) before Rett syndrome gradually became universally recognized.
Following the genetic discovery, medical research skyrocketed as animal models came to fruition, increasing the possibility of treatments and cures that had never been possible before. At the same time, researchers in the field of education and communica- tion pushed forward with much greater understanding of the potential for learning. Today, we are rewriting the history of Rett syndrome! No longer are girls sentenced to languish without education, relegated to wheelchairs without the benefit of therapy. No longer are they expected to remain silent with no means of communication. And for the very first time, there is real hope, not just for those born today, but even for those born long ago; hope that the disabling and painful symptoms of Rett syndrome can be not only ameliorated, but possibly eradicated.
As I look forward to the promise of a better tomorrow for my daughter, Stacie, I realize how very much I owe her. She has given me strength I never knew I had, but more importantly, she has shown me how to turn tragedy into triumph. While others may remark on my patience, I remind them that Stacie is the one who eats when I think she is hungry, goes to bed when I think she is tired, and continually endures my clumsy attempts to figure out by trial-and-error what hurts her. I look at her with eyes of love and see the power of her powerlessness, the strength and courage of the life she lives without the value of one spoken word. And then I realize that she is who she is, and that she touches others in a miraculous way, not by what she can do, but by what she cannot. I find myself stronger, richer, fuller, and so much more appreciative because she has taught me to recognize the smallest gifts that others take so easily for granted. Beyond all of this, Stacie and others like her deserve better lives and I know that they all join me in looking forward to changing the sentence that once defined us, ‘What is Rett syndrome?’ to ‘What was Rett syndrome?’”
We are commemorating more than 50 years since Andreas Rett’s initial publication describing the syndrome carrying his name. In these five decades we have acquired a remarkable amount of information about the clinical features of the disorder, its etiology, and its pathophysiology. Much less progress has been made in terms of interventions, although some recommendations for specific management are available and the number of ongoing and planned clinical trials is increasing.
Realistic and meaningful management objectives
Several models have been suggested to explain the ‘natural history’ of Rett syndrome, from arrested development to stage systems, though the current trend tends to focus on individual developmental trajectories, activities of daily living, quality of life, and specifically tailored objectives. Thus, there is slowly increasing knowledge about how to select realistic and meaningful management objectives, how to pursue them and evaluate outcomes—from promoting physical activity and appropriate nutrition, to therapy and surgical interventions.
On the verge of effective disease-modifying treatment
Tremendous hope has also been fostered by findings in animal models and the development of targeted therapy aimed at the MECP2 gene and its expression or downstream factors, such as neurotransmitters or neurotrophic factors. Several clinical trials are currently being carried out, with some promising early results.
Finally, the history of Rett syndrome also exemplifies the power of family support groups. It shows how collaboration between clinicians, researchers and support groups can contribute to the improvement of knowledge, and the development of appropriate information for patients, health professionals and the general public, as well as promote access to screening and diagnostic testing.
It is certain that Andreas Rett never foresaw the revolution he started, with great help from Bengt Hagberg, by identifying the first affected individuals. Rett syndrome is now not only a disorder but a field, a model neurological disease, and a gene (MECP2) that plays a crucial role in synaptic development and function.
* Excerpted from the book Rett Syndrome edited by Walter E Kaufmann, Alan Percy, Angus Clarke, Helen Leonard and SakkuBai Naidu.
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