Angelman Syndrome

Author: Christine Ma

Editor: Leah Farquharson



Angelman Syndrome (AS) is a rare neurological disorder that affects 1 in every 12,000 to 20,000 live births (Madaan & Mendez, 2021). There are different subtypes with varying degrees of severity including deletion phenotype, paternal disomy, and an imprinting phenotype (Margolis et al., 2015). AS is quite rare, but affects races and genders equally (Madaan & Mendez, 2021). AS has many symptoms, especially severe cognitive disability, speech impairments, motor dysfunction, hyperactivity, and sleep impairment (Margolis et al., 2015). Current treatments are symptom-based and include pharmacological treatment, therapies, and bracing (Wheeler et al., 2017). 



There are 4 molecular mechanisms that may cause AS, which have been determined by human genetic studies (Margolis et al., 2015). 

  • The first and most common mechanism which is seen in around 70-80% of cases is a de novo maternal deletion of chromosome 15q11-q13 (Margolis et al., 2015). Those with AS caused by the first mechanism described above generally have the most severe presentations (Madaan & Mendez, 2021). 
  • The second most common mechanism that occurs around 10-20% of the time is an intragenic mutation in the maternally inherited UBE3A gene, which results in a nonfunctional version of the ubiquitin-protein ligase E3A, the mutation is within chromosome 15q11-q13 (Margolis et al., 2015). 
  • The third mechanism is present in around 3-5% of patients, paternal uniparental disomy which occurs in chromosome 15q11-q13 (Margolis et al., 2015). 
  • The fourth mechanism, present in around 3-5% of patients, is called an imprinting defect and occurs in chromosome 15q11-q13 (Margolis et al., 2015). An imprinting defect may result in an alteration of the UBE3A gene, a maternally inherited gene (Margolis et al., 2015). 


Generally, those with a deletion phenotype have a more severe presentation of AS compared to those with paternal uniparental disomy or imprinting mutation (Margolis et al., 2015). The non-deletion phenotype of AS is generally milder both clinically and behaviourally (Pearson et al., 2019). Individuals with non-deletion etiologies generally have increased communication and abilities compared to those with deletion etiologies (Pearson et al., 2019). 



AS is a rare disease, and is seen in 1 in every 12, 000 to 20,000 live births (Madaan & Mendez, 2021). Other studies show AS affects 1 in every 10, 000 to 62 000 live births (Wheeler et al., 2017). AS affects both males and females equally (Madaan & Mendez, 2021). 



Symptoms may be reported as early as 6 months, and some symptoms may become progressively severe over time and develop with age (Wheeler et al., 2017).

  • Severe cognitive disability
  • Frequent seizures (majority of individuals have onset of seizures prior to age 3)
  • Speech impairment (may entirely lack speech or can speak few words)
  • Receptive language may or may not be impaired
  • Motor dysfunction (tremors, jerkiness, ataxia)
  • Hyperactivity
  • Short attention span
  • Happy demeanor with easily provoked or excessive laughter
  • Mouthing of objects
  • Attraction to water
  • Decreased sleeping (Margolis et al., 2015)
  • Aggression and irritability (Wheeler et al., 2017)
  • Protruding tongue, tongue thrusting, suck/swallowing disorders
  • Wide mouth with widely spaced teeth
  • Frequent drooling
  • Hypopigmented (fair skin, light hair, light eyes)
  • Hyperactive lower extremity deep tendon reflexes
  • Increased sensitivity to heat
  • Strabismus (eyes do not seem to align/ focus)
  • Scoliosis
  • Abnormal food behaviors
  • Truncal hypotonia
  • Prognathism (underbite) (Madaan & Mendez, 2021)


Risk Factors

Genetic predisposition plays a major role in the development of the AS since it is usually caused by disruption of the maternally expressed and paternally imprinted UBE3A, where a genetic mutation within the UBE3A results in a nonfunctional E3 ubiquitin ligase (Margolis et al., 2015, Madaan & Mendez, 2021). Studies have shown the crucial role of the E3A ubiquitin-protein ligase in synaptic development and the deficiency of this protein leads to AS pathophysiological in humans, however, the mechanism of the development is still poorly understood and need further research studies (Margolis et al., 2015). 


Subfertile couples (with or without fertility treatments) may be at an increased risk for birthing individuals with the imprinting phenotype of AS (Ludwig et al., 2005). Subfertile couples are defined as a couple with more than two years of time to pregnancy and/or fertility treatments (Ludwig et al., 2005). 



Diagnosis of AS may be started in the prenatal stage when a fetus presents with growth restrictions (Madaan & Mendez, 2021). The non-invasive prenatal testing (NIPS) technique has been shown to be quite accurate when diagnosing AS in the prenatal stage (Madaan & Mendez, 2021). 

Post-birth, diagnosis of AS may be more complicated (Madaan & Mendez 2021). Overlapping features of AS and other neurological diseases may hinder the diagnosis process of AS (Margolis et al., 2015). AS diagnosis must be confirmed molecularly (Margolis et al., 2015).

Methylation studies and fluorescence in situ hybridization (FISH) must be performed when AS is suspected to confirm the diagnosis (Madaan & Mendez, 2021). Methylation studies are used to determine if the individual’s maternal Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) exon 1 region/promoter is methylated, and in most AS cases is unmethylated (Madaan & Mendez, 2021). FISH is performed after methylation studies and detects deletions in maternal chromosome 15 (Madaan & Mendez, 2021). If negative, imprinting defects may be considered by molecular studies, and paternal disomy may be considered by DNA marker analysis (Madaan & Mendez, 2021).

DNA sequencing may be done if an individual displays a negative methylation study, and can rule out mutations in the UBE3A gene (Madaan & Mendez, 2021). An electroencephalogram (EEG) can also be helpful in showing seizure activity and can show the characteristic AS pattern (Madaan & Mendez, 2021). Sleep studies may be used to determine sleep disorders (Madaan et al., 2021). 


Clinical features

One of the first signs of AS is restricted growth as a fetus (Madaan & Mendez, 2021). The majority of patients also have seizures (Wheeler et al., 2017). Patients may also have a speech impairment, increased aggression, and general autism symptoms (Margolis et al., 2015). Many individuals with AS are hyperactive (Margolis et al., 2015). AS patients also often display a wide mouth with widely spaced teeth, although this is not visible until the patient has teeth (Madaan & Mendez, 2021). Sleep difficulties, especially with falling asleep and staying asleep, are often prevalent in individuals with AS (Wheeler et al., 2017). Individuals may also have scoliosis (Madaan & Mendez, 2021). 


Pathological features

Patients with AS often have mutations in their UBE3A gene (Madaan & Mendez, 2021). Often, DNA studies must be performed to determine these mutations (Madaan & Mendez, 2021). The majority (around 80%) of AS patients do not have a methylated maternal SNRPN exon 1 region/promoter (Madaan & Mendez, 2021). This can be confirmed by methylation studies (Madaan & Mendez, 2021).

Deletions may be present in maternal chromosome 15 in the case of the deletion phenotype of AS and can be determined with FISH (Madaan & Mendez, 2021). In cases of the imprinting phenotype, imprinting will be present and can be determined with molecular studies (Madaan & Mendez, 2021). Those with the paternal disomy phenotype may display abnormal DNA markers, and this can be determined with DNA marker analysis (Madaan & Mendez, 2021). 


Treatment protocol

Treatment of AS is usually symptomatic (Madaan & Mendez, 2021). Generally, an introduction of a specific individualized intervention plan is a useful treatment for individuals with AS (Madaan & Mendez, 2021). Movement disorders are currently treated with physiotherapy, occupational therapy, bracing as needed and changes in diet to prevent obesity (Wheeler et al., 2017). Speech impairments can be treated with augmentative or alternative communication systems as well as enhancing nonverbal communication (Wheeler et al., 2017). Speech and language therapy may also help for verbal and nonverbal speech, and computers are a recent technology that has improved the communication of those with AS (Madaan & Mendez, 2017).

Behavioral interventions may be required for inappropriate behavior such as excessive laughing, aggressing, and irritability (Wheeler et al., 2017). Increasing communication outputs may help as an outlet to counteract the patient’s hyperactivity (Wheeler et al., 2017).

Pharmacological treatment may be required for individuals struggling with seizures, aggression, or anxiety (Wheeler et al., 2017). For those with sleep impairments, the use of melatonin, improvement of the sleep environment, adjustment of sleep-wake cycles, reinforcement of bedtime routine, and independent sleep initiation may be of help (Wheeler et al., 2017).


Articles on misdiagnosis

Darteyre, S., Mazzola, L., Convers, P., Lebrun, M., & Ville, D. (2011). Angelman syndrome and pseudo-hypsarrhythmia: a diagnostic pitfall. Epileptic disorders : international epilepsy journal with videotape, 13(3), 331–335.

Hussain Askree, S., Hjelm, L. N., Ali Pervaiz, M., Adam, M., Bean, L. J., Hedge, M., & Coffee, B. (2011). Allelic dropout can cause false-positive results for Prader-Willi and Angelman syndrome testing. The Journal of molecular diagnostics : JMD, 13(1), 108–112. 

Tan, W. H., Bird, L. M., Thibert, R. L., & Williams, C. A. (2014). If not Angelman, what is it? A review of Angelman-like syndromes. American journal of medical genetics. Part A, 164A(4), 975–992. 

Williams, C. A., Lossie, A., Driscoll, D., & R.C. Phillips Unit (2001). Angelman syndrome: mimicking conditions and phenotypes. American journal of medical genetics, 101(1), 59–64. 



Ludwig, M., Katalinic, A., Gross, S., Sutcliffe, A., Varon, R., & Horsthemke, B. (2005). Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples. Journal of medical genetics, 42(4), 289–291. 


Madaan, M., & Mendez, M. D. (2021). Angelman Syndrome. In StatPearls. StatPearls Publishing.


Margolis, S. S., Sell, G. L., Zbinden, M. A., & Bird, L. M. (2015). Angelman Syndrome. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 12(3), 641–650.


Pearson, E., Wilde, L., Heald, M., Royston, R., & Oliver, C. (2019). Communication in Angelman syndrome: a scoping review. Developmental medicine and child neurology, 61(11), 1266–1274. 


Wheeler, A. C., Sacco, P., & Cabo, R. (2017). Unmet clinical needs and burden in Angelman syndrome: a review of the literature. Orphanet journal of rare diseases, 12(1), 164. 


Print this Article

Mini Disclaimer

User discretion: The material presented here is for your information and to be used for your reference only. Our volunteers have sourced this information from reputable sources and made sure it meets the quality standards at MARI. The information presented is not intended to be used as a diagnostic tool, a basis upon which to make diagnostic decisions, or to substitute the advice of a medical or healthcare professional. 

If you are a patient experiencing any of the listed symptoms, please consult a healthcare provider for specialized care and follow the instructions provided for you by your doctor. If you are in the US and would like advice on a possible case leading to errors in medicine, please reach out to our MARI Consultation team.

We appreciate your feedback!

Thank you for visiting our website. We are always looking for ways to improve. Please take a moment to tell us about your experience.