Angelman Syndrome

Epidemiology and Background

Angelman syndrome is a complex genetic disorder with significant neurodevelopmental consequences, most commonly associated with speech impairment and ataxia. It affects between 1/10,000-1/20,000 individuals.


Angelman syndrome is an imprinting disorder involving a region on chromosome 15. Genomic imprinting is the process of expressing only one of a pair of genes via epigenetic modification. The expression pattern depends on the parent of origin (i.e. maternal vs paternal chromosome). Imprinting occurs during gametogensis and <1% genes are imprinted.

The genetic defect in Angelman syndrome is loss of function of maternally expressed UBE3A gene that encodes an E3 ubiquitin ligase. This gene is located in chromosomal region 15q11.2-q13 that is also responsible for Prader-Willi syndrome (PWS). In PWS, there is a loss of paternal expression of other imprinted genes (see separate page on PWS). 

There are four molecular mechanisms in which the maternal UBE3A allele may become dysfunctional.

  1. Most commonly there is a 5-7MB de novo deletion within maternal chromosomal region 15q11.2-q13 (~75% of cases), the size of which depends on which breakpoints are involved. Deletions between more distant breakpoints lead to more severe disease – Class I is a deletion between breakpoints 1 and 3, whereas Class II is a deletion between breakpoints 2 and 3, and hence leads to less severe disease.
  2. Paternal uniparental disomy (UPD) is a situation in which both copies of chromosome 15 come from the father and zero from the mother. Because both copies of UBE3A are consequently imprinted and silenced, there is no enzyme activity. This accounts for 1-2% of cases. 
  3. Nonsense/missense mutations of the maternally derived UBE3A gene can lead to dysfunctional or nonfunctional protein activity. These mutations are present in 5-10% of patients with Angelman syndrome. 
  4. In 1-3% of cases, imprinting defects cause the maternally inherited chromosome to adopt the methylation patterns and associated gene expression of a paternally inherited chromosome, leading to gene silencing. The majority of defects are epigenetic changes with normal DNA sequence; only a small subset are caused by imprinting center deletions. 


The neurodevelopmental findings associated with Angelman Syndrome are not usually noted at birth, but can be identified more commonly at age 6-12mo when patients' psychomotor delay becomes apparent and parents note a lack of crawling and babbling. Patients often don't walk until they are 3-4 years old and display a distinctive jerky, puppet-like gait. Many of the clinical findings can be explained by the fact that the maternal allele is the exclusively active allele in the cerebellum and hippocampus.

Neuropsychiatric findings abound and patients are characterized by severe intellectual disability. There is little to no speech development. Patients exhibit extreme hyperactivity and attention deficits, which puts them at risk for accidental injuries. Children with Angelman Syndrome are noted to be particularly happy and affectionate, craving interpersonal relationships. They are easily excitable and have frequent episodes of laughter and smiling, even during inappropriate times. 

By age 2-3 years, more than 80% of patients have seizures and abnormal EEGs with large amplitudes and slow spiked waves, even in the absence of active seizures. Patients also have significantly difficulty with sleep, with altered sleep cycles and trouble sleeping more than 5 hours at a time.


Physical Manifestations

Physical manifestations include delayed motor development followed by movement and balance disorders, most commonly ataxia, muscular hypotonia with hyperreflexia, and tremulous limb movement. Patients often suffer feeding difficulties in infancy with poor suck and swallow. Children may develop hand-flapping movements and hypermotor tendencies (including frequent mouthing behavior). Patients will often walk with jerky body movements, a stiff legged gait, and arms in the air.

A happy five-year-old girl with Angelman syndrome. Features shown include telecanthus, bilateral epicanthic foldssmall head, wide mouth, and a playful demeanor; hands with tapered fingers, atypical creases and broad thumbs.

Physical findings include postnatal microcephaly, small flat occiput, a protruding thrusting tongue, prominent jaw, strabismus, and hypopigmentation of the skin, hair, and eyes. Interestingly, patients with Angelman Syndrome demonstrate a curious fascination with water.

The severity of these findings depends on the class of deletion – a larger deletion (Class I) is associated with greater difficulty in expressive language, the need for more anticonvulsants, and a higher incidence of autism spectrum disorder.

Differential Diagnosis

When considering a patient with the findings associated with Angelman Syndrome, other considerations may include:

A thorough history and physical should help to narrow the list of possible diagnoses.


Workup for suspected Angelman Syndrome starts with thorough history and physical. The first-line diagnostic test is DNA methylation analysis, which captures ~80% of cases. 

If the methylation studies are positive, the next step is to determine whether the condition is class I or II via microarray to delineate the extent of deletion. If the arrays are negative, then uniparental disomy (UDP) should be ruled out using microsatellite DNA markers or SNP arrays. If UDP studies are negative, imprinting center studies should be conducted.  These mutations may be familial/inherited or sporadic epimutations that do not demonstrate any alteration in the DNA sequence. Individuals may also display mosaicism.

If all methylation studies return negative and the healthcare practitioner is still concerned for Angelman Syndrome, a full DNA sequence of UBE3A can be performed to identify more rare mutations.

Screening, Monitoring, and Management

A thorough developmental evaluation should be conducted when Angelman Syndrome is first suspected, and once diagnosed, this evaluation will assist in the management of symptoms.

An EEG should be conducted to check for seizures only after one year of symptoms with Angelman Syndrome, because the findings will always be abnormal in the first year of life. Anticonvulsants should be provided for seizure control. Unfortunately, the selection of a regimen proves difficult as patients suffer from several types of seizures, as opposed to a more unified set of seizures found in traditional epilepsy. Melatonin or clonidine can be provided to assist with severe sleep disturbances. The patient should also be evaluated for feeding problems and gastroesphagal reflux at an early age.

Referral to physical, occupational, speech, and behavioral therapy have proved to be extremely helpful in reducing the morbidity and burden of disease. Physical therapy has been especially helpful to maintain joint mobility and movement. Speech therapy can assist with augmented communication methods.

Over time, hyperactivity and poor sleep improve and seizures decrease with age. While intellectual disability persists throughout life, with proper social support, patients can live relatively normal lifespans. Patients typically cannot live independently but can frequenly learn basic household tasks and live in group homes.

Ongoing Research

Significant research efforts are underway in the area of Angelman syndrome. Most efforts focus on ways to unsilence the dormant paternal UBE3A gene to compensate for loss of function of the maternal allele. The first successful trial used the topoisomerase inhibitor topotecan (published in Nature in 2012). However, the drug's toxicity and inhibition of off targets make it unlikely to become standard treatment. A more recent study (published in Nature in 2015) used RNA interference by antisense oligonucleotides (ASOs) that demonstrated both in vitro and in vivo efficacy in a mouse modelThese ASOs function to eliminate a non-coding RNA that blocks expression of the paternal allele.

Other studies are looking at drugs that can be used for symptomatic control. Ovid Therapeutics began a phase 3 clinical trial in 2019 to test the use of OV101 (gaboxadol), a GABA-A agonist that has been shown to improve sleep, behavior, and motor deficits in adolescents and adults with Angelman syndrome. There was hope that the use of vitamin supplements such as folic acid and betaine could alleviate symptoms, but trials were unsuccessful.   

Practitioner and Patient Resources

Many resources are available to help once the diagnosis of Angelman Syndrome has been made.

The Angelman Syndrome Foundation provides significant support for families affected by Angelman Syndrome. It also provides information on the most up-to-date research. More information is available at the link BELOW:


Information and resources for healthcare practitioners is available through the NIH and can be found at the links BELOW:




Buiting, K., Williams, C. & Horsthemke, B. Angelman syndrome — insights into a rare neurogenetic disorder. Nat Rev Neurol 12, 584–593 (2016).

Huang, H., Allen, J., Mabb, A. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481, 185–189 (2012).

Meng, L., Ward, A., Chun, S. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518, 409–412 (2015).