Angelman syndrome (AS) is a rare neurogenetic disorder that affects approximately one in 15,000 people – about 500,000 individuals worldwide. Children and adults with AS typically have impaired motor and balance, and debilitating seizures. Some individuals never walk. The majority do not speak. Disrupted sleep cycles also can be a serious challenge to the individual and caregivers. Individuals with AS require continuous care and are unable to live independently. They have a normal life expectancy. People with Angelman syndrome have some distinct behavioural traits, including a happy demeanour, characterised by frequent laughing, smiling and excitability. Many individuals with AS have a fascination with water and take great pleasure in activities like swimming.
For people with Angelman syndrome, this maternal UBE3A gene is not doing its job, and that impacts their Messenger RNA (mRNA). Our DNA uses mRNA as a delivery service to send blueprints to the protein-assembly factories of our cells. People with AS have a mutation, deletion or another defect in their UBE3A gene that interrupts this delivery service. As a result, their neurons do not make any functional UBE3A protein, and that’s what triggers the symptoms of AS. This protein is what helps us walk, talk and perform other everyday tasks.
In most cases, Angelman syndrome isn’t inherited – particularly those caused by a deletion or UPD. Instead, these genetic changes occur as random events during the formation of reproductive cells or in early embryonic development.
- 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 individuals with AS.
- 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 functional 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 centre on Chromosome 15, but cases can also be cause 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 unrecognised 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 (see right menu).