Angelman Syndrome

By:  Catherine Joachin

Photo credit: www.depositphotos.com

What is Angelman syndrome?

Angelman syndrome (AS) is a genetic condition characterized by developmental delays,  underdeveloped speech, ataxia, and seizures (Cleveland Clinic., n.d.). It affects around 500,000  people globally and emerges as a result of UBE3A dysfunction (Angelman Syndrome  Foundation, n.d.). The condition was first described by Dr. Harry Angelman in 1965 (Angelman  Syndrome Foundation, n.d.).

Causes and Symptoms

Angelman syndrome is generally caused by issues with the maternal copy of chromosome 15’s ubiquitin-protein ligase E3A (UBE3A) gene (Cleveland Clinic, n.d.). Since the paternal copy of  UBE3A is inactive, any changes to the expression of maternally-inherited genes (e.g., mutation,  deletion) can lead to the neurodevelopmental defects observed in AS (NHS, 2023).

Signs of developmental delays can be observed by 6 to 12 months of age, while other symptoms including poor motor skills and gastrointestinal issues tend to appear in early childhood (Angelman Syndrome Foundation, n.d.). Symptomology varies; however, people tend  to present some rather than all characteristics associated with the condition (Boston Children’s  Hospital, n.d.)

Common symptoms of Angelman syndrome include:

• Stiff, jerky body movements

• Little or no functional speech

• Feeding problems, especially in infancy

• Delays in motor development

• Seizures

• Developmental delays, including no crawling or babbling

• Intellectual disability

• Difficulty walking, moving or balancing

(Boston Children’s Hospital, n.d.; Mayo Clinic, 2022)

In addition, children with the disorder may display the following:

• Frequent unprovoked outbursts of laughter

• Hand-flapping motions and walking with uplifted arms

• Restlessness/hyperactivity

• Trouble sleeping

• A particular fascination with water

• An excitable, friendly nature

(NHS, 2023)

These particular symptoms tend to fade with age as children develop better sleep patterns and become less hyperactive (Cleveland Clinic, n.d.). In some cases, people with Angelman  syndrome may possess distinctive facial features including crossed eyes, paler complexion,  wide mouth, scoliosis, widely spaced teeth, protruding tongue, and a small flat head (Cleveland  Clinic, n.d.)

Diagnosis

Angelman syndrome is often misdiagnosed by virtue of sharing several characteristics with other disorders (Angelman Syndrome Foundation, n.d.). These include cerebral palsy, Prader-Willi syndrome and autism, Mowat-Wilson syndrome, Christianson syndrome, Pitt-Hopkins syndrome, and Phelan-McDermid (Cleveland Clinic, n.d.).

Genetic testing can be harnessed to mitigate this issue by investigating changes in the  UBE3A gene (Mayo Clinic, 2022). These tests aim to determine whether chromosomes are missing, or mutated, or if genetic chromosomal defects have been passed on (Cleveland Clinic,  n.d.). Electroencephalogram and polysomnography tests may be administered to diagnose or verify the extent of related complications such as disordered sleeping (Cleveland Clinic, n.d.).

Treatment and Management

Angelman syndrome is a life-long condition, but it does affect life expectancy (Cleveland Clinic,  n.d.). Children affected by this condition require constant care and will be unable to live independently as adults (Angelman Syndrome Foundation, n.d.).

While there is currently no cure for Angelman syndrome, early intervention can help alleviate symptoms and provide access to helpful tools and services.  

• Physical therapy, which can improve posture, mobility, and balance.

• Behavioral therapy to manage unsolicited behavior

• Communication aids and speech therapy can help people with Angelman syndrome learn and interact better via sign language, gesturing, and technology.

• Anticonvulsant medication for seizure management

(Cleveland Clinic, n.d.)

Epilepsy in Angelman syndrome

The majority (80-90%) of people with Angelman syndrome experience seizures (Conant, Thibert  & Thiele, 2009; Thibert et al., 2012). For these individuals, epilepsy commonly presents itself in the form of atypical absences, generalized tonic-clonic, atonic, or myoclonic seizures, which can be hard to manage (Fiumara et al., 2010). 

There is little definitive information on the pathogenesis of epilepsy in Angelman syndrome,  however, researchers have hypothesized that GABA receptors impaired by UBE3A deletion  might be responsible for abnormal neural activity observed in AS patients (Pelc et al., 2008)

Sleep disturbances, a common feature of Angelman syndrome, are also linked to epilepsy. In a  study by Conant and colleagues (2009), unhygienic sleep behaviors were associated with the presence of multiple seizure types, however, it remains unclear whether poor sleep patterns exacerbate epilepsy or if epilepsy leads to poor sleep hygiene.

In terms of medical care, research suggests that low glycemic index treatment, a dietary therapy used to control epilepsy, could potentially be implemented as a treatment option for AS-related seizures (Thibert et al., 2012). Other studies suggest that lamotrigine therapy should also be considered for treating AS-related refractory seizures due to the drug’s inverse pharmacodynamic effect (Dion et al., 2007).

Conclusion

AS is a rare neurodevelopmental condition that severely affects people’s behavior,  communication skills, and motor functioning. Nearly all individuals with this disorder experience seizures. Fortunately, these can generally be managed with the help of antiepileptic medication.

References

Angelman Syndrome Foundation. (n.d.). What is Angelman Syndrome – Angelman Syndrome  Foundation. Angelman Syndrome Foundation. Retrieved from https://www.angelman.org/what is-as/

Boston Children’s Hospital. (n.d.). Angelman Syndrome. Boston Children’s Hospital. Retrieved  from https://www.childrenshospital.org/conditions/angelman-syndrome

Cleveland Clinic. (n.d.). Angelman Syndrome. Cleveland Clinic. Retrieved from https:// my.clevelandclinic.org/health/diseases/17978-angelman-syndrome#outlook-prognosis

Conant, K. D., Thibert, R. L., & Thiele, E. A. (2009). Epilepsy and the sleep–wake patterns found in Angelman syndrome. Epilepsia (Copenhagen), 50(11), 2497–2500. https://doi.org/ 10.1111/j.1528-1167.2009.02109.x

Dion, M.-H., Novotny, J., Carmant, L., Cossette, P., & Nguyen, D. K. (2007). Lamotrigine therapy of epilepsy with Angelman’s syndrome. Epilepsia (Copenhagen), 48(3), 593-. https:// doi.org/10.1111/j.1528-1167.2006.00969.x

Fiumara, A., Pittalà, A., Cocuzza, M., & Sorge, G. (2010). Epilepsy in patients with Angelman syndrome. Italian Journal of Pediatrics, 36(1), 31–31. https://doi.org/10.1186/1824-7288-36-31

Mayo Clinic (2022). Angelman syndrome – Symptoms and causes – Mayo Clinic. Mayo Clinic.  Retrieved from https://www.mayoclinic.org/diseases-conditions/angelman-syndrome/symptoms causes/syc-20355621

National Health Service (2023). Angelman syndrome. National Health Service. Retrieved from: nhs.uk. https://www.nhs.uk/conditions/angelman-syndrome/

Pelc, K., Boyd, S. G., Cheron, G., & Dan, B. (2008). Epilepsy in Angelman syndrome. Seizure  (London, England), 17(3), 211–217. https://doi.org/10.1016/j.seizure.2007.08.004

Thibert, R. L., Pfeifer, H. H., Larson, A. M., Raby, A. R., Reynolds, A. A., Morgan, A. K., &  Thiele, E. A. (2012). Low glycemic index treatment for seizures in Angelman syndrome.  Epilepsia (Copenhagen), 53(9), 1498–1502. https://doi.org/10.1111/j.1528-1167.2012.03537.x

Read More