What is Angelman syndrome?

Angelman Syndrome (AS) is a rare neurogenetic disorder affecting approximately 1 in every 15,000 people - about 500,000 individuals worldwide. Children and adults with AS have balance issues, motor disabilities, and may experience debilitating seizures. Some individuals never walk. Most do not speak. Disturbed sleep can also pose a serious challenge for the individual and their caregivers.

Individuals with AS require ongoing care and are unable to live independently. They have a normal life expectancy. This is the current life of people living with Angelman Syndrome, but there is hope. Scientists believe that AS has the highest potential for cure compared to any other neurogenetic disorder. (FAST, 2023)

Characteristics

The typical characteristics of AS are not usually evident at birth. Individuals with this condition may have feeding difficulties as infants and noticeable developmental delays around 6-12 months of age. They require intensive therapies to help develop functional skills. Angelman Syndrome affects all races and both genders. It is often mistakenly diagnosed as autism or cerebral palsy.

Behavioral Aspects

People with Angelman Syndrome often exhibit unique behavioral characteristics, including a joyful demeanor characterized by frequent laughter, smiling, and excitement. Many individuals with AS have an affinity for water and greatly enjoy aquatic activities such as swimming and bathing. It is important to note that Angelman Syndrome is a spectrum disorder, and as such, not all individuals exhibit the same behavioral characteristics or preferences.

Diagnosis

The journey to diagnosing Angelman Syndrome is not always easy. There is no definitive age for diagnosis, but thanks to scientific advances and rigorous infant screenings, diagnosis is occurring faster and earlier. The presentation of Angelman Syndrome varies according to the individual's genotype.

Causes of Angelman Syndrome

Angelman Syndrome is caused by a loss of function of the UBE3A gene on the 15th maternal chromosome. People have two sets of chromosomes - one inherited from the mother and the other from the father. In a typical person, the UBE3A gene inherited from the mother is active, while the copy of the gene inherited from the father is silenced in the neurons of our brain - a phenomenon known as imprinting. In individuals with AS, this maternal gene is not performing its function, impacting its Messenger RNA - mRNA. (FAST, 2023)

What is mRNA?

In our bodies mRNA carries genetic instructions from DNA to the protein-making machinery within cells. In individuals with Angelman Syndrome there is a defect in the maternal UBE3A gene, which disrupts mRNA. Consequently, their neurons fail to produce functional UBE3A protein, leading to the symptoms associated with AS. This protein is crucial for enabling basic functions such as walking, talking, and carrying out everyday activities.

Is it hereditary?

Angelman Syndrome is not hereditary in most cases, however, there are exceptions. To learn more about hereditary aspects of Angelman Syndrome, click here.

Genotypes

All conditions of Angelman Syndrome involve an anomaly of the UBE3A gene on the 15th maternal chromosome.

However, there are various distinct types of genetic anomalies that can occur in the UBE3A gene, called "genotypes."

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Aspects of each genotype:

Neurotypical

(without Angelman syndrome)

In typical individuals, UBE3A is expressed in most tissues from chromosome 15, both paternal and maternal alleles.

In neurons, the paternal allele of the UBE3A gene is silenced by a natural process of genomic imprinting. As a result, only the maternal allele is active in the neurons of neurotypical individuals.

Deletion

(65-75%)

Most individuals with AS have a piece of DNA missing ("deleted") in the 15q11-13 region of the maternal chromosome 15.

Individuals living with SA deletions generally lack the UBE3A gene along with 8 to 12 other genes. This means that 5 to 6 million base pairs of DNA are missing on the maternal chromosome 15. The other missing genes also contribute to tonic inhibition, seizures, lighter coloring, and much more. Overall, this makes the characteristics of those living with deletion SA generally more severe than other genotypes.

Mutation

(5-11%)

Some individuals live with AS because they exhibit a difference (a "change") in the UBE3A gene. Each gene is composed of chemicals called nucleotides that form DNA. The nucleotides in DNA, called A, C, T, and G, are arranged in a very specific order that the cell reads to form the UBE3A protein. A difference in the nucleotides of DNA is called a variant, also known as a mutation. In these individuals, a mutation in the UBE3A gene prevents it from expressing or functioning properly.

There are different types of mutations in UBE3A, or variants. To learn more details about the types of mutations, click here.

Uniparental Disomy - UPD

(3-7%)

An individual with UPD has two paternal copies of chromosome 15 instead of one paternal and one maternal.

Imprinting Center Defect - ICD

(<3%)

The imprinting center is a small stretch of DNA located in the q11-13 region of the chromosome. In rare cases, the maternal chromosome 15 is blank, and the center copies the paternal chromosome 15. This constitutes an imprinting defect.

Mosaicism

(~1%)

Genetic mosaicism is an extremely rare genotype of Angelman Syndrome, where a small proportion of the body's cells express UBE3A. A person with mosaicism has a mix of body cells—some fully express UBE3A and others do not express UBE3A at all. Most reported cases estimate 5-20% of cells with maternal expression, although reports range from 1 to 40%. (FAST, 2023)

Watch this educational video for an overview:

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Genetic Testing

There are different types of genetic tests to determine a diagnosis of Angelman Syndrome. The specific test required for diagnosis depends on the individual's genotype. DNA methylation testing can detect 80% of AS cases. The remaining 20% require other specific tests, such as: complete exome sequencing, UBE3A gene sequencing, FISH, among others.