First identified in 1965 by British pediatrician, Dr. Harry Angelman. Angelman Syndrome was initially referred to as “Happy Puppet Syndrome,” due to the happy disposition and unique gait of those affected.

In 1997, Dr. Arthur Beaudet discovered mutations to the UBE3A gene on the 15th chromosome to be the cause of Angelman Syndrome.

Each individual living with Angelman Syndrome is unique, with their own set of strengths and challenges. It is important to note that AS is a spectrum disorder, and that the symptoms and their severity can vary greatly from person to person.

Consistent characteristics of AS include:

• Developmental delay

• Movement or balance difficulties

• Speech impairment

• Unique behaviours; frequent laughter, smiling, excitable

Frequently observed characteristics include:

• Seizures

• Abnormal EEG

• Delayed or disproportionate growth in head circumference

Other associated characteristics include:

• Feeding problems

• Abnormal sleep / wake cycles

• Chewing / mouthing behaviours

• Constipation

• Strabismus

Humans have 46 chromosomes in each cell of their body, with 23 inherited from the mother and 23 from the father. The underlying cause of AS is the loss of a functional UBE3A gene, which is located on the 15th chromosome.

Some genes on a chromosome are active (expressed), while others remain inactive (silent). In typical individuals, the UBE3A gene inherited from the father is silent in the brain, while the UBE3A gene from the mother plays a crucial role in brain function and development. In individuals with AS, the maternal UBE3A gene is nonfunctional.

There are different genetic causes or mechanisms of AS, these are also known as ‘genotypes’. Understanding the specific genotype not only helps guide medical and therapeutic management, but also provides information for families regarding recurrence risk and genetic inheritance patterns. The following are the known ways in which the UBE3A gene is disrupted, inactive or absent:

• Deletion (70–75% of cases)
  This is the most common cause of Angelman syndrome, where a segment of chromosome 15, including the maternal UBE3A gene, is missing. Deletion cases are not hereditary and typically occur as a random event during the formation of reproductive cells or early embryonic development.

• UBE3A Mutation (10–11% of cases)
  This involves a change in the DNA sequence of the maternal UBE3A gene, disrupting its normal function. Mutations can sometimes be inherited, particularly if a parent carries a genetic alteration that predisposes them to passing on the mutation.

• Uniparental Disomy (UPD) (3–5% of cases)
  UPD occurs when an individual inherits both copies of chromosome 15 from their father and none from their mother, resulting in no active maternal UBE3A gene. This happens due to an error during the formation of reproductive cells or early development.

• Imprinting Center Defect (ICD) (2–3% of cases)
  This rare defect affects the region of DNA responsible for regulating whether the maternal or paternal UBE3A gene is active. In individuals with ICD, the maternal gene is silenced, leading to AS. Imprinting defects can sometimes be inherited, particularly if a parent carries a similar imprinting issue.

• Mosaicism (1–2% of cases)
  Mosaicism occurs when the genetic alteration is present in only some cells, resulting in a milder or variable presentation of symptoms. This can happen when the genetic change arises after fertilization during early embryonic development. Because not all cells are affected, individuals with mosaicism are less affected than the other genotypes.

Genetic testing for AS can be complex, and has evolved over the years. There are several genetic tests that can help diagnose AS by identifying abnormalities in the UBE3A gene. These are often used in combination to confirm a diagnosis of AS, including the specific genetic mechanism (genotype). Key diagnostic tests include:

• Methylation Analysis: This is often the first step in testing. It identifies whether there is a problem with the UBE3A gene's imprinting or methylation. In AS, the paternal copy of UBE3A is usually silenced, and the maternal copy is active. If both copies appear inactive, this suggests a problem.

• Chromosome Microarray (CMA): This test identifies deletions or duplications on chromosome 15 that might affect the UBE3A gene.

• UBE3A Sequencing: This test examines the UBE3A gene itself for smaller mutations not detected by methylation analysis or CMA.

• Fluorescence In Situ Hybridization (FISH): This test identifies large deletions or structural abnormalities on chromosome 15.

• Imprinting Center Defect Testing: This test detects specific defects in the region responsible for genomic imprinting on chromosome 15.