Angelman Syndrome


Epidemiology and Background

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

The condition is due to the genetic phenomenon known as genomic imprinting. In these cases, there exists a differential expression of genetic information depending on whether a gene allele has been inherited from the mother or the father. In the case of Angelman Syndrome, there is an interstitial chromosomal deletion between 15q11 and 15q13 on the maternally derived chromosome 15, leading to an absence of the maternally inherited copy of the UBE3A gene, which codes for E6 associated ubiquitin protein ligase 3A.

The lack of a functional maternal copy of UBE3A leads to Angelman Syndrome even if the paternal chromosome 15 and allele are normal – the paternal copy is “imprinted” and therefore silenced. In genomic imprinting, the sex of the parent transmitting the damaged gene is relevant, rather than the sex of the offspring; an active maternal allele is required to avoid development of Angelman Syndrome. There are no known risk factors that increase the likelihood of a dysfunctional maternal allele.

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

  1. Most commonly there is a large deletion up to 4MB (70% 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.
  3. Imprinting center defects can cause the maternally inherited chromosome to adopt the methylation patterns and associated gene expression of a paternally inherited chromosome, leading to gene silencing.
  4. Much more rarely, nonsense/missense mutations of the maternally derived UBE3A gene can lead to dysfunctional or nonfunctional activity.



The neurodevelopmental findings associated with Angelman Syndrome are not usually noted at birth, but can be identified more commonly at age 6-12mo when parents note a lack of crawling and babbling. 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. However, 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 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.



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.

Click on the video BELOW to watch a child with Angelman Syndrome:


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, followed by a karyotype and FISH analysis to assess for any missing chromosomes. If no gross abnormalities are present, the next step of investigation should be methylation studies and a chromosome microarray (array CGH) to characterize methylation patterns (in actuality, the methylation studies look at the methylation of the neighboring gene SNRPN rather than UBE3A itself).

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 be postzygotic mosaics.

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. Mouse studies have shown impairments in hippocampal memory formation and loss of synaptic plasticity in CA1 region, which may help to explain some pathophysiology. A recent study published in Nature is looking at the use of topoisomerase inhibitors to unsilence the dormant UBE3A allele (available at ( Another group is evaluating whether vitamin supplements such as folic acid and betaine can alleviate the symptoms of Angelman Syndrome by increase the activity of UBE3A. Mouse model studies are attempting to investigate whether therapeutic intervention using CaMKII signaling – which may be disrupted in AS – may be of any benefit.


Much more research is being conducted and can be found at the link BELOW:



Practitioner and Patient Resources

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


The NIH maintains a list of patient resources, found at the link BELOW:



In particular, the Angelman Syndrome Foundation provides significant support for families affected by Angelman Syndrome. 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: