About Angelman Syndrome

About Angelman Syndrome

What is Angelman Syndrome?

Angelman syndrome (/'e?nd??lm?n/; abbreviated AS) is a neuro-genetic disorder characterized by severe intellectual and developmental disability, sleep disturbance, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling, and usually a happy demeanor. AS is a classic example of genomic imprinting in that it is caused by deletion or inactivation of genes on the maternally inherited chromosome 15 while the paternal copy, which may be of normal sequence, is imprinted and therefore silenced. The sister syndrome, Prader-Willi syndrome, is caused by a similar loss of paternally inherited genes and maternal imprinting. AS is named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965.[1] An older, alternative term for AS, "happy puppet syndrome", is generally considered pejorative and stigmatizing so it is no longer the accepted term, though it is sometimes still used as an informal term of diagnosis.[citation needed] People with AS are sometimes known as "angels", both because of the syndrome's name and because of their youthful, happy appearance.

Angelman syndrome is a complex genetic disorder that primarily affects the nervous system. Characteristic features of this condition include delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy) and a small head size (microcephaly). Delayed development becomes noticeable by the age of 6 to 12 months, and other common signs and symptoms usually appear in early childhood.

Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. Hyperactivity, a short attention span, and a fascination with water are common. Most affected children also have difficulty sleeping and need less sleep than usual.

With age, people with Angelman syndrome become less excitable, and the sleeping problems tend to improve. However, affected individuals continue to have intellectual disability, severe speech impairment, and seizures throughout their lives. Adults with Angelman syndrome have distinctive facial features that may be described as "coarse." Other common features include unusually fair skin with light-colored hair and an abnormal side-to-side curvature of the spine (scoliosis). The life expectancy of people with this condition appears to be nearly normal.

What 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.

Is 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.

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.

References: Foundation for Angleman Syndrome Therapeutics (FAST)