What is Angelman Syndrome?
What causes Angelman Syndrome?
Is there hope for a cure?
What is Angelman Syndrome?
Want more information on the genetics of Angelman Syndrome and what all those medical terms mean? Please see our Genetics 101 section
Angelman Syndrome (or AS) is a neurodevelopmental disorder characterized by global developmental delays and severe speech impairment. A few individuals with AS develop functional speech but most communicate through a mixture of gestures, eye gaze, adapted sign language and augmentative communication devices.
Individuals with AS have developmental delay and intellectual disabilities. Current research suggests that neuronal development occurs correctly in the brain in AS, but neuronal functioning is impaired. This neuronal impairment impacts the individual's ability to learn in that skills are acquired less rapidly than in age-matched peers. However AS individuals continue to progress throughout their lifespan, and their ability to learn is greatly enhanced by intensive educational programs, repetition, and environmental enrichment.
Individuals with AS have a movement and balance disorder which ranges from mild to severe. While some children with Angelman walk before age 3, most walk much later and some never achieve independent walking. The movement disorder can be mild and only affect gait and hamper some fine motor skills, or severe enough to prevent self-help skills like feeding, walking, and dressing.
Most individuals with AS have a seizure disorder which can be difficult to treat. Feeding disorders in infancy are common and some persist throughout childhood. Sleeping difficulties are commonly noted in individuals with AS. Individuals with AS tend to have a happy demeanor, characterized by frequent laughing, smiling and excitability. Many indviduals with AS have an unusual attraction to water and take great pleasure in water based activities like swimming and bathing.
TopWhat causes Angelman Syndrome?
Angelman Syndrome is caused by a severe reduction of expression of the gene UBE3a in the brain. UBE3A is a ubiquitin ligase whose function and targets relevant to AS are still unknown.
Want more information on the genetics of Angelman Syndrome and what all those medical terms mean? Please see our Genetics 101 section
15q11.2-q13 deletions (~68% of cases) - the majority of AS cases are caused by deletions on the maternal copy of Chromosome 15. Due to genomic imprinting, only the maternal copy of UBE3A is expressed in the brain. The deletion thus removes the normal expression of this gene in AS individuals.
UBE3A mutations (~11% of cases) - In these individuals, mutations in the UBE3A gene either prevent its expression or function. Thus these individuals do not have the appropriate levels of fuctional UBE3A in the brain.
Uniparental disomy (UPD; ~7% of cases) - in UPD, the individual has two copies of paternal Chromosome 15. Because UBE3A is not expressed from the paternal copy, these individuals lack normal levels of UBE3A in the brain.
Imprinting defect (~3% of cases) - These individuals may have a deletion of the imprinting center an Chromosome 15, but cases can also be caused by loss of imprinting information during the mother’s oogenesis. Loss of imprinting will prevent expression of the maternal UBE3A gene in the brain.
Clinical/other (~11%) - In these individuals, all testing for Angelman Syndrome is normal, but they still meet the diagnostic criteria for AS. These individuals may have as yet unrecognized mutations that affect UBE3A or genomic imprinting on Chromosome 15. Please note that there are several other syndromes that present like AS that can be tested for.
Summarized from GeneReviews on Angelman Syndrome by C.A. Williams and D.J. Discoll
TopIs there hope for a cure?
The number of scientific researchers and breadth of knowledge about the genetics, neurobiology, and biochemistry of Angelman Syndrome has significantly expanded in the past decade. As of August 2008, close to 1000 articles on Angelman Syndrome were listed in Pubmed; the premier database of scientific studies. Visit our Current Research page to view a selection of these articles.
Through research we know that Angelman Syndrome is caused by a lack of functional levels of UBE3A protein in neurons. This appears to have multiple effects on how neurons function, in particular how well neurons of the brain communicate information to each other during memory formation; known as synaptic plasticity. For individuals with Angelman Syndrome, this leads to something resembling a profound learning disorder. Learning occurs, but more slowly than in age matched peers resulting in global developmental delays.
For many childhood developmental disorders, it is unclear what specific genetic or environmental causes underlie the disorder. Much of the current research is spent trying to understand the molecular mechanisms of these disorders. Thus, research towards a cure is seriously hampered by this lack of knowledge. However, this is simply not the same situation with AS. Because we know the cause of AS is a loss of functional levels of UBE3A in the brain we already possess the basic knowledge we need to start the search for a viable treatment.
When thinking about a viable treatment or "cure" for Angelman Syndrome, one concern has always been that the lack of UBE3A expression during fetal development may result in irreversible damage to brain structures. While still a concern, recent research suggests that neurons retain their ability to function normally and can be persuaded to do so under the correct conditions. For example, in a mouse model of Angelman Syndrome, combining a mutation in UBE3A with a mutation in another important protein (CamKII) rescued the severe neurological and motor defects in this model. For more details on this exciting research read the article in either Nature Neuroscience or Spectrum Magazine. While we still need to determine if the same rescue can occur in adult mice, this report alone suggests medications aimed at the CamKII pathway have potential to treat individuals with Angelman Syndrome.
In addition, the current animal models provide invaluable tools that will allow for screening of experimental pharmaceutical precursors and existing drugs to determine if any of these compounds can activate the silenced paternal copy of the UBE3A gene in the brain.
Our current knowledge of how AS occurs, recent cutting-edge research, and a growing partnered commitment by parents and scientists present a significant hope for finding a cure for Angelman Syndrome only imagined a few years ago. We want everyone to be a part of this journey.
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