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Angelman Syndrome

Understanding Angelman & What Causes it

Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by genetic alterations that primarily affect the nervous system. It is characterized by severe developmental delays, movement and balance disorders, speech impairment, seizures, and unique behavioral traits, such as a frequent happy demeanor. AS results from the loss of function of the maternal UBE3A gene on chromosome 15q11.2-q13, which
plays a critical role in brain development and synaptic function.

Key characteristics of Angelman Syndrome include:

  • Developmental Delays: Children often experience significant delays in reaching developmental milestones, starting at infancy.
  • Difficulty communicating: Individuals typically have minimal or no spoken language
  • Movement and Balance Disorder: Ataxia (poor coordination), tremors, and unsteady gait. Hyperkinetic movements (jerky, excitable movements, excessive hand flapping). Hypotonia (low muscle tone) in infancy often transitions into ataxia and hypermotoric behavior in early childhood.
  • Seizures and EEG Abnormalities: Many individuals with Angelman Syndrome experience seizures, which can vary in type and frequency. See section on Epilepsy for more details
  • Sleep: Sleep concerns are common in, with 20–80% of individuals having a decreased sleep need and/or abnormal sleep–wake cycles.
Symptom Support & Resources

Information on how to manage the above can be found at our Support & Resources page

Genotypes

There are a few ways that Angelman Syndrome can occur. These are called genotypes. Each genotype has a different mechanism that results in AS.

70%

Deletion positive

Large deletion of maternal UBE3A and other genes. The most common variation and unfortunately, this tends to be the most severe, in terms of symptoms or characteristics.

  • Inheritance & Recurrence Risk: De novo (not inherited)
  • Clinical Severity: Most severe phenotype
5%

Imprinting Center Defect

Maternal UBE3A gene is silenced due to an imprinting defect. The imprinting center is the area of the chromosome that controls whether genes are turned on or off.

  • Inheritance & Recurrence Risk: Can be inherited if deletion present
  • Clinical Severity: Variable severity
11%

Mutation

Mutation in maternal UBE3A gene, preventing function.

  • Inheritance & Recurrence Risk: UBE3A mutation can either occur spontaneously (e.g., not inherited and with no increased recurrence risk) or be maternally inherited and have a 50% risk of recurrence
  • Clinical Severity: Milder than deletion
3-5%

Paternal Uniparental Disomy (UPD)

This occurs when there are two paternal copies of chromosome 15, but no maternal copy. Since the UBE3A from the father is silenced or turned off, and the one from the mother is absent, the brain cannot get the information it needs from UBE3A.

  • Inheritance & Recurrence Risk: De novo, low recurrence risk
  • Clinical Severity: Milder than deletion
1%

Mosaic

A very small number of people with AS have a “mosaic” form of AS, whereby a percentage of cells in the brain have a normal copy of the maternal Ube3a. Individuals with this type of AS tend to have a milder form of the disorder.

  • Inheritance & Recurrence Risk: De novo
  • Clinical Severity: Milder, highly variable
10%

Clinical Diagnosis or Unknown

When individuals who have apparent normal genetic tests (no evidence for deletion, imprinting defect, UPD or UBE3A mutation) however the clinician feels that the presentation closely fits the traits of AS.

Traits & Characteristics

People with Angelman Syndrome (AS) often exhibit a combination of distinctive facial features, behavioral traits, and developmental characteristics. While these traits can help in recognizing AS, it is important to remember that each individual is unique, and the severity and presentation of symptoms can vary widely.

  • Broad Mouth and Wide Smile (Macrostomia): A characteristically broad mouth with a wide smile, often accompanied by widely spaced teeth.
  • Prominent Chin (Mandibular Prognathism): A pronounced chin and jawline, which often becomes more noticeable during puberty and adulthood.
  • Microcephaly (Small Head Circumference): Many individuals with AS develop microcephaly, meaning their head size is smaller than average for their age. In some cases, this is associated with a flatter occiput (the back of the skull).
  • Deep-set Eyes and Periorbital Hypopigmentation: The eyes may appear more deeply set, and some individuals have light-colored skin around the eyes (periorbital hypopigmentation), contributing to a distinctive facial expression.
  • Light Skin, Hair, and Eye Color (in UBE3A Deletion Cases): Many individuals, particularly those with a UBE3A gene deletion, have lighter-colored skin, hair, and eyes due to the associated loss of the OCA2 gene, which is involved in pigmentation. However, this varies depending on ethnic background and individual genetic differences.

Some common behavioral characteristics may include:

Individuals with Angelman Syndrome often exhibit a unique behavioral phenotype, which may include:

  • A joyful and happy demeanor with frequent smiling and laughter. This is one of the hallmark characteristics of AS.
  • Hyperactivity and Hypermotoric Behavior: Restlessness, an inability to sit still, easy distractibility, and excessive movement are common in childhood. However, hyperactivity often decreases with age.
  • Hand Flapping and Sensory-Seeking Behaviors: Many individuals engage in hand flapping, repetitive movements (stimming), and sensory-seeking behaviors such as excessive laughter, fascination with textures, or repetitive visual stimuli.
  • Fascination with Water, Music, and Shiny Objects: A strong attraction to water, rhythmic sounds (music), and reflective or shiny objects is commonly reported.
  • Sensitivity to Heat: Some individuals may have heat intolerance, which can contribute to discomfort, irritability, or behavioral changes in warmer environments.
  • Feeding Difficulties in Early Life: Infants may struggle with gastroesophageal reflux, poor suck-swallow coordination, tongue thrusting, and frequent drooling.
  • Excessive Chewing and Mouthing Behaviors: Many children and adults with AS exhibit prolonged chewing, biting, and mouthing behaviors, which may be linked to sensory processing
    differences.

The combination of distinct facial features, behavioral traits, and developmental challenges helps clinicians and families recognize Angelman Syndrome, though each individual presents differently. The severity and presentation of these traits may vary based on the underlying genetic cause (genotype).

References & Further Reading:

Since Angelman Syndrome (AS) can arise from different genetic mechanisms, multiple testing methods are required to confirm a diagnosis. No single test can diagnose or rule out all forms of AS, so a combination of genetic tests is typically performed based on clinical suspicion and initial findings.
If AS is strongly suspected but not confirmed through first line testing, additional specialized genetic tests may be necessary.

To confirm a diagnosis of Angelman syndrome, your child’s doctor will perform a combination of genetic tests that can include the following:

  • Chromosomal microarray analysis (CMA) is a high-resolution whole-genome screening test, which detects small genetic alterations that are too small to be identified by conventional karyotyping or FISH. 
    • CMA is the preferred first-line test for detecting the characteristic 15q11.2-q13 deletion seen in approximately 70% of AS cases.
    • SNP-based CMA can also detect some cases of uniparental disomy (UPD), but only when isodisomy (two identical copies from one parent) is present.
    • CMA cannot determine whether the detected deletion is maternal or paternal, so additional DNA methylation testing is often required to confirm AS.
  • FISH to see if any chromosomes are missing. Now most genetics specialists recommend CMA or MLPA so that the size of the deletion can be determined.  
  • DNA methylation test to see if both copies of a gene — one from the mother and one from the father — are active. It is one of the most important tests for diagnosing AS, as it can detect 80% of cases (those caused by UBE3A deletions, UPD, or imprinting center defects).
    • A characteristic DNA methylation pattern confirms a diagnosis of AS in individuals with deletion, UPD, or imprinting defects.
    • However, methylation testing does NOT detect UBE3A gene mutations (~10% of AS cases), so
      if results are normal but AS is still suspected, UBE3A sequencing is performed.
  • UBE3A sequencing: to look for a mutation in the maternal mutation of this gene, which is a rarer cause of Angelman syndrome (about 10% of individuals)
  • MS-MLPA This test method can check the DNA methylation AND look for deletions at the same time.  Consequently, it can confirm the diagnosis of AS for individuals who have typical AS deletions, UPD, ICD deletions, and ICD methylation, and it can provide the genotype for typical AS deletions and the ICD deletion genotypes
  • ICD Deletion Testing: This test is typically performed when an individual has methylation testing consistent with AS but does not have a 15q11.2-13 deletion or UPD.  ICD deletion testing may also be included as part of MS-MLPA.   
  • Whole exome sequencing (WES) and whole genome sequencing (WGS) are used when a diagnosis is unclear or when a healthcare provider is considering multiple genetic conditions.
    • WES/WGS can detect UBE3A mutations, but analysis methods vary between laboratories.
    • Some WES/WGS methods may detect deletions (similar to those seen in AS), but not all labs reliably detect UPD or methylation abnormalities.
    • If parental samples are provided, some WES/WGS tests may identify UPD, but this depends on the laboratory's testing methodology.
    •  If WES/WGS has been performed, the genetics team should consult with the laboratory to determine which AS genotypes were ruled out.

This material was extracted from FAST (Foundation for Angelman Syndrome Therapeutics). Highly Recommended deep dive reading at FAST Testing 101 and FAST Testing and Diagnosis

Infants with AS commonly present with nonspecific psychomotor delay and/or seizures and so the differential diagnosis is often broad and nonspecific, encompassing entities such as cerebral palsy, developmental delay, and abnormal movements. Tremulousness and jerky limb movements seen in most infants with AS may help to distinguish AS from these conditions Williams et al (2010)

With advancements in genomic technology, it has become clear that some individuals who initially test negative for AS actually have alternative genetic diagnoses. Approximately 10% of individuals with clinical features suggestive of AS do not have a confirmed genetic diagnosis of AS upon standard testing. These cases are often referred to as Angelman-like syndromes because they share overlapping clinical and behavioral features.

Some of the most common differential diagnoses for Angelman Syndrome include:

  • Mowat-Wilson syndrome
    • Features include intellectual disability, epilepsy, characteristic facial features, and congenital heart defects.
    • Movement abnormalities and a happy demeanor may overlap with AS.
  • Christianson syndrome
    • Characterized by intellectual disability, ataxia, epilepsy, microcephaly, and an unusually happy disposition, similar to AS.
    • Unlike AS, it typically leads to progressive neurodegeneration.
  • Pitt-Hopkins syndrome
    • Features include developmental delay, severe speech impairment, characteristic facial features, and intermittent breathing abnormalities (episodic hyperventilation or breath- holding).
    • Seizures, ataxia, and happy demeanor can overlap with AS.
  • Rett syndrome
    • Shares features with AS in early childhood, including developmental regression, hand stereotypies (e.g., hand-wringing), absent speech, and seizures.
    • Key difference: Rett syndrome is associated with progressive loss of motor skills and communication, autonomic dysfunction, and distinct EEG patterns.
  • Prader-Willi syndrome
    • Genetically related to AS (both involve chromosome 15q11-q13), but distinct in presentation.
    • Key differences:
      • AS: Hyperactivity, happy demeanor, ataxia, severe speech impairment.
      • PWS: Neonatal hypotonia, poor feeding in infancy, later onset of excessive appetite (hyperphagia), and obesity.
    • Diagnosed through the same methylation test used for AS, as it reveals an opposite imprinting defect.
  • Phelan-McDermid Syndrome (22q13 Deletion Syndrome)
    • Caused by deletions or mutations in the SHANK3 gene.
    • Characterized by hypotonia, absent or severely delayed speech, intellectual disability, and autism spectrum traits.
    • Key difference: Lacks the characteristic happy demeanor of AS and is more associated with autism and self-injurious behaviors.