Angelman syndrome (AS), is a rare neurodevelopmental disorder that results in severe intellectual disability with minimal expressive language, autistic features in some individuals, an abnormal gait, tremors, sleep difficulties, and a unique behavioral profile characterized by frequent laughter, fascination with water, mouthing of objects, and short attention span.
Angelman syndrome was first described in 1965 by Harry Angelman, a British pediatrician. A person with AS cannot live independently at any point in their lives, requiring constant care and supervision. When Dr. Angelman first observed children with this disorder, he named it “the Happy Puppet syndrome,” in an effort to capture a visual picture in words of his observations: the staggering walk with arms uplifted and the often smiling, happy demeanor of people with AS. “The Happy Puppet Syndrome” was later renamed Angelman syndrome through the efforts of Dr. Charles Williams, a leading researcher on AS in the U.S. and his colleagues at the University of Florida.
Dr Williams writes: “In 1986, I decided to establish the Angelman Research Group (ARG) for the purpose of facilitating research on and education about AS. At that time, AS was a syndrome of unknown cause and not even the deletion on chromosome 15 was known to be associated with it. The financial support for the ARG came from the Raymond C. Philips Research and Education Unit at the University of Florida. By 1990, the ARG would eventually become the U.S. Angelman Syndrome Foundation (ASF).”
The Angelman Syndrome Foundation has grown into a thriving foundation, sponsor of yearly events, scientific symposia, and numerous ongoing research projects in AS.
Jill Hendrickson, a genetics counselor, and Elaine Whidden, a nurse, worked with Dr. Williams to start the Angelman Research Group, which recruited families of children with Angelman, developing a database of subjects and publishing articles about AS. Their work eventually culminated in the creation of the consensus criteria for AS in 1995.
In 1987, Joseph Wagstaff, Children’s Hospital in Boston, and Art Beaudet at the University of Texas, discovered the genetic cause of AS and the relationship of this genetic cause to the UBE3a protein. Even with breakthroughs in genetics, many individuals who have Angelman syndrome remain undiagnosed because genetic testing cannot be applied unless the disorder is first suspected clinically. It has historically been a long and difficult process for families to obtain the correct diagnosis for rare disorders, and this holds true for Angelman syndrome. Another issue is the concern for the health of future children or grandchildren – some forms of AS are hereditary, and it is crucial for families to understand the genetic background so that appropriate family planning can occur. Early diagnosis is not only desirable; it is critical if the best treatment is to be obtained, including appropriate therapies and most successful medications for seizures. But early diagnosis is not easy to achieve.
The Angelman Project video production teams created a series of short documentaries on 73 children and adults with Angelman syndrome by following them throughout their daily lives in their usual environments, including their homes, schools, and work centers. This resulted in an indexed video database of the various clinical features of Angelman syndrome including documentaries presented by a wide range of experts — neurologists, geneticists, genetics counselors, psychologists, therapists, teachers and others.
Two hour-long documentaries featuring a wide range of subjects with AS of different ages are presented by Jill Clayton Smith in Manchester, England and Charles Williams at the University of Florida,. Dr. Clayton-Smith and Dr. Williams, both world-recognized authorities and researchers in Angelman syndrome, also had clinical practices with many patients with AS.
See Clip 1: excerpt from Diagnosing Angelman Syndrome, presented by Charles Williams, MD.
In addition, there are hundreds of short clips displaying observations of the symptoms and behaviors associated with AS.
See Clip 2: Walking Stairs, Katie, (Del+) Ages 8 & 12.
The Angelman Project was funded by a NIH R44 (Small Business Innovation Research) grant. The filming was carried out with Jill Hendrickson, Phase 1 Principal Investigator and Timothy Freeman, Phase II Principal Investigator. Each subject was filmed over several days in multiple locations – school, home, therapist’s office, and others. The filming included on camera interviews – sometimes extensive – with family as well as related clinicians and therapists. Observational examples of gait, happy demeanor, cranio-facial appearance and other aspects of AS, were edited into 100’s of separate short video clips – offering an outside observer an opportunity to compare various short clips on these different features between subjects and to have a much clearer sense of the symptoms as expressed in different individuals – different ages, and with different levels of disease severity.
Full-length documentaries, narrated by clinicians as well as family members, were also created. Experts explained aspects of the diagnosis, and interventions. Families shared stories about the difficulties they faced getting the diagnosis and offered their observations on life with a person with AS, as well as their often very carefully worked out strategies for daily living.
After the first films were edited, themes came into focus– such as the difficulty of getting a diagnosis, finding the right support systems for their children, dealing with the impact of Angelman syndrome on the life of the family, Not all seizure medications are effective for AS and some seizure medications can actually cause additional seizures in individuals with AS. Parents frequently described the difficulty in getting help for their children’s seizures:
See Clip 3: Seizures: featuring Alex, (Del+) Age 2.5. Alex’s parents detail the history of Alex’s seizures, the search for proper care and medication, coping with the Emergency Room process. Footage of Alex having a seizure at 2.5 years old is included.
Parents without a diagnosis tended to confront many blind alleys in seeking care. Early diagnosis also allows parents and concerned others to connect with support systems for assistance. It’s comforting to know you’re not alone, to speak with someone else who shares your concerns and can also share solutions. Without support systems, without connection to experts, the process of obtaining care can be a daunting one.
Documentary videos are at the heart of the GeneticaLens protocol (The See System). Our approach follows the “participant-observer” model used in anthropological field studies. We videotape the everyday routines of our subjects– at home, or in school, or in the community. Our production crews try to blend into the environment, yet we do not stay aloof – we interact with everyone, but sparingly, so that their daily interactions with each other (when a film crew is not present) become the center of attention and of our filming.
See Clip 4: Sharon’s Behaviors at Bessent Group Home, featuring Sharon, (UBE3A) Observational Documentary of some of Sharon’s behaviors such as hugging and dancing, also shows some of her communication skills, vocal and signing; and her energy. Commentary by Tanjala and Celena, staff at the group home.
To facilitate earlier diagnosis and treatment, it is essential that doctors and other professionals understand in greater detail not only the main features of the appearance of Angelman syndrome and what affected individuals have in common, but also the basic aspects of their behaviors and abilities at different ages — behaviors, which, as families already know, are more complex and variable than may at first be apparent.
Once we have acquired our raw footage, there are many processes applied during the logging process. Our output formats include observations, interviews with — with knowledgeable informants — parents, siblings, therapists, peers and related professionals and clinicians.
At the end of the Angelman Project, GL editors had created over 400 videos, including 59 documentaries and over 250 clips on all aspects of AS, and had completed 35 DVD projects.
In 2000, after viewing a demo of the Angelman Project, Dr. Jeremy Silverman (Mt Sinai School of Medicine) wrote:
“Seeing video examples of numerous Angelman kids really brought home to me that…[they] would likely fulfill criteria for autism …video examples of the characteristic Angelman’s gait helps a diagnostician like myself to better abstract what is characteristic to the syndrome from what is specific to a particular child with the syndrome.”
The power of video to teach was clear.
Natural history studies of rare and difficult to diagnose disorders are becoming more and more critical as research uncovers a wide range of promising palliative and – when the genetic cause is known – targeted therapies for these disorders. Angelman syndrome (AS) is no exception and, in fact, genetic studies have uncovered genetic descriptions for AS, which have in turn led to possible targeted therapies for AS. But it is difficult to know precisely how either palliative or targeted therapies affect a disorder without a comprehensive understanding the baseline clinical profile of the disease and its variations in affected individuals.
Such a clinical profile consists of many types of data and observations – but perhaps most helpful in understanding the disorder is the ability to see similarities in individuals with AS and… differences. For example, there are similarities in people with AS regarding disposition, gait, intellectual disability and the possibility of seizures. And then there are differences between individuals with AS – differences in level of disease severity, variations due to differences in genetic description and also variations due to changes over time. Some individuals with AS can speak a few words – others can only make sounds. This difference could be one of a difference in genetic cause. Whatever the cause, videotape is particularly helpful in capturing similarities and differences because video captures not just an isolated symptom or behavior, but the symptom or behavior in the context of daily living.
See Clip 5: Distractibility/Short Attention Span, featuring Ben (UPD).
Video clips of symptoms and behaviors filmed in a wide variety of situations, combined with data from medical and psychological assessments are invaluable in establishing these similarities and differences. Indeed a “picture” of a disorder emerges and a way of mapping what is “typical” for that disorder and how these “typical” elements appear with different backdrops and in different contexts — at home or in school; during different stages of life, toddler to adult. Further, video can capture those sometimes subtle differences in personality and approach to life that vary in all people, including those with rare disorders.
This process of building a mix of videos showing individuals with AS in different settings and with different people allows the creation of a more evidence-based set of criteria in setting clinical endpoints for use in prescribing palliative therapies, as well as for use in setting goals for proposed targeted therapies.
Beginning with an observant clinician with a small practice, and the naming of children who shared certain unusual characteristics: the smiling demeanor, lack of expressive language but ability to understand language, the staggering gait — the study of AS has evolved – beginning with a handful of symptoms, progressing to an understanding of the genetic causes. Today families of individuals with AS are becoming more and more involved in funding research and teaming up with clinicians to start new initiatives, everything from the development of new research projects, to discoveries of more effective therapies. As a result of these efforts, current research in possible interventions for AS are in progress, including studies by Ben Philpot, PhD, at University of North Carolina, and a clinical trial of levodopa in Angelman syndrome, sponsored by Wen-Hann Tan.
These studies (and others) potentially offer the prospect of new interventions for this serious disorder. The reality of targeted therapies is still at a distance, but the fact that research may be pointing the way via a greater and greater understanding of the genetic expressions of AS to possible interventions and even cures, offers hope to countless families who have dedicated many years to making the best possible life for their children, often at great sacrifice.
There are many roadblocks to progress. In order to develop effective interventions, it is necessary to understand the nature of a disease and how it progresses over time. But because there are fewer patients with confirmed diagnoses, it is hard to observe clinical signs in the course of a practice or as part of a research study. Further, there are many variables — making the understanding of the symptoms of AS challenging – there are different genetic expressions, with different levels of disease severity, further complicated by changes over time, with multiple outcomes in different individuals.
But the ability to understand the clinical diagnoses and to describe the nature and characteristics of AS is essential if genetic explorations and development of interventions is to succeed. And well-characterized visual data with a platform for entering and cataloguing new data is of fundamental importance to all concerned – researchers who are setting milestones and forming hypotheses for setting new clinical endpoints; clinicians who must be able to recognize symptoms in patients who come to their offices and clinics; families who must know what to expect at each stage of life, so they can seek the best help and therapies and make plans for the future.
Dr. Angelman appreciated the importance of visual cues and the importance of recognizing similarities in his patients’ appearance and symptoms. The Angelman Research Group in creating the consensus criteria began a system of characterization of AS that would not only stimulate genetic research, but also present parents all over the world with a set of clear criteria – concrete and visual – that would help them seek help for their children and eventually stimulate the forming of AS groups and organizations the world over.
Today the progress made in understanding AS involves the efforts of multiple groups — university researchers, clinicians, the teachers, therapists, parents and caregivers. The teamwork is critical to all phases of research – families are the caregivers and need to be case managers, and families also are often the organizers and contributors to the resources that make research possible.
With involvement from so many sources, and with the need for participation by various specialists – neurologists, geneticists, pediatricians and many others – it is critical to mobilize the latest digital technologies — social networking, new video technologies, cloud-based HIPAA compliant servers, and other web-based advances — and make these available worldwide. What we are proposing is a collaboration that will bring the various constituencies together, creating a flexible, accessible and powerful platform for data and video entry, a technologically based innovative system to help drive forward new research as well as new uses of the research to positively affect the lives of those with AS and their families.
The creation of SeeSystem-AS by GeneticaLens and the RDCRN – AS as part of the Natural History Study now in progress will more effectively address many of the unanswered questions about Angelman syndrome and the impact that it has on the affected individuals and their families, in a way that snapshots captured through questionnaires at each Natural History visit would not be able to.