Angelman syndrome

Definitions & Key takeaways

Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by problems with motor skills, speech, developmental delay, and learning disabilities. People with AS typically have happy dispositions and frequently laugh or smile, even when they are not engaged in activities that would typically elicit such reactions.

Most individuals with AS do not develop fluent speech, have sleep disturbance, and usually have seizures. People with AS typically have a normal life expectancy and have the potential to improve on some self-help skills with proper supportive care.

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Angelman syndrome is a genetic disorder that causes intellectual and developmental delay, seizures, frequent laughter, and ataxia, or poor control of voluntary movements.
Now, it happens when a gene on chromosome 15 called UBE3A is not expressed, or transcribed into messenger RNA. UBE3A stands for ubiquitin-protein ligase E3A, and the protein it codes for is called E6AP or E6-associated protein.
The job of E6AP is to go around tagging, or attaching, a tiny protein called ubiquitin to other proteins, a process called ubiquitination.
Once that happens, the ubiquitinated protein is degraded by the proteasome, a part of the cell’s recycling machinery. It’s kind of painting an orange U on a tree so that a lumberjack knows to chop it down.
So E6 associated protein has an important job, and it turns out that the region of chromosome 15 around UBE3A is imprinted, imprinting refers to gene expression that’s dependent on the parent of origin of a gene.
This means that either the maternally derived or paternally derived copy of the gene is silenced. This differs from most genes in the genome, where both the maternal and paternal copies are expressed.
Normally, in the brain, only the maternally derived copy of UBE3A is expressed, while the paternal copy is silenced, unfortunately this process of imprinting leaves the maternal copy of UBE3A vulnerable.
So with the paternal copy of the gene imprinted, and epigenetically silenced, you’ve only got the maternal copy left. So this means that if anything happens to the maternal copy, the result is Angelman syndrome.
There are a few different types of mutations that can cause Angelman syndrome. The most common one is a deletion of a couple million base pairs of DNA on the maternal copy of chromosome 15 which includes UBE3A.
Sometimes the deletion overlaps a nearby gene called OCA2, which codes for a pigment that gives color to eye, hair, and skin.
As a result of this, these Angelman syndrome patients can have a light complexion. A second way is a mutation within the maternal copy of UBE3A, making the protein ineffective.
A third way to get Angelman syndrome is when the entire maternal chromosome 15 is absent and instead there’s an extra copy of the paternal chromosome 15.
This scenario is called paternal uniparental disomy, which means that one parent – the father – contributed two of the same chromosome while the mother contributed none.
Because of the one-for-one exchange, there isn’t an aneuploidy, or abnormal chromosome number. But this does mean that both chromosomes are epigenetically marked as being from dad, so UBE3A is turned off.
A final type of mutation causing Angelman syndrome is called an imprinting defect. In this case the maternal chromosome 15 gets mistakenly methylated, which ultimately causes the UBE3A gene to be silenced.
This might be caused by part of an error in oogenesis, or egg development, or because of a mutation in the imprinting center, which is an epigenetic control sequence.
Most cases of Angelman syndrome are sporadic, meaning that they’re caused by a new mutation. Epigenetic inheritance, though, can lead to some interesting pedigrees, where the parent-of-origin is what’s important in who gets the disease.
For example, a UBE3A mutation passed down from a father is asymptomatic, since that copy would be turned off anyway. You might think that a deletion on chromosome 15 or maternal uniparental disomy of chromosome 15 would also be asymptomatic.
But, it turns out there are other important genes next to the angelman syndrome region that are imprinted in the opposite way to UBE3A – meaning only the paternally-derived ones are expressed.
So in this case if those paternal genes are lost, like with deletion or maternal uniparental disomy, then it results in a different disease, called Prader-willi syndrome, and this is the reason this part of chormosome 15 is called the Prader-Willi-Angelman region.
In infancy, Prader-Willi syndrome causes low muscle tone and poor feeding, while later on causes overeating and obesity later on, low IQ, and inadequate genital development.
Infants and children with Angelman syndrome have delayed development, meaning that it might take them months or years longer than other children to achieve a specific milestone like sitting independently.
Most children with Angelman syndrome never learn to speak, and although most do learn how to walk, they’re often unsteady and tend to walk with arms flexed and hands pronated so that the palm is facing downward to the ground.
Other common features include seizures, difficulty with sleep, a small head size, a fair complexion, and scoliosis. Children with Angelman syndrome are often happy, excitable, and have hand-flapping movements.
But these are also common among children in general, so they’re only noteworthy when other symptoms are present. There is no cure for Angelman syndrome, so problems are addressed one by one, for example communication boards can be used for the absent speech.
All right as a quick recap, Angelman syndrome is an imprinting disorder, where the expression of UBE3A on the maternal copy of chromosome 15 – which is the only copy expressed in the brain – is compromised, causing severe intellectual disability, seizures, laughter, and ataxia.