Angelman Syndrome

What is Angelman syndrome?

Angelman syndrome is a rare, genetic, neurodevelopmental condition estimated to affect 1 in 15,000 people.1 First described in 1965 by English pediatrician Dr. Harry Angelman, Angelman syndrome causes delayed development, intellectual disability, behavioral deficits (like anxiety, irritability and hyperactivity), severe speech impairment, problems with movement and balance, seizures and sleep disorders.2-4 Many symptoms that develop early in childhood persist into adulthood and can evolve as a person ages.2,7 While individuals with Angelman syndrome are highly social with a typical lifespan, they require constant support from a network of specialists and caregivers.2,3,8

Angelman syndrome affects males and females equally, and the genetic cause has been traced to a loss of function of the ubiquitin protein ligase E3A (UBE3A) gene.2,5,8

Neuronal dysregulation results in significant impairments that can be difficult to manage

Angelman syndrome or another condition?

The first signs of Angelman syndrome are usually developmental delays that appear in the first year, such as lack of crawling or walking.3,6 Angelman syndrome is commonly diagnosed at 2 to 5 years of age, when characteristic behaviors and features are most evident, but presentation and severity can vary greatly between patients and evolve with age.5,9,10 Due to its similarity to other conditions, it is frequently misdiagnosed; however, social demeanor really sets Angelman syndrome apart from other conditions. Characteristic features of Angelman syndrome include excessive laughter and a happy demeanor, and children with Angelman syndrome typically enjoy being around other people and want to communicate and form personal interactions.2

Individuals with Angelman syndrome have a typical life span, but require consistent care, as severe symptoms persist throughout life. As a result, caregivers need to provide constant supervision, especially due to challenging behaviors of patients. This puts a significant personal stress on caregivers, who often report pain, anxiety and exhaustion.11-14

Current treatment options

To date, there are no therapies specific to those with Angelman syndrome. Management of Angelman syndrome is largely limited to supportive care. Following diagnosis, families of individuals with Angelman syndrome are often referred to specialists, therapists and specialized school programs for assistance with walking and movement, social engagement and communication strategies.8

Disease management strategies used today do not target the underlying neurological pathophysiology of Angelman syndrome, thought to be due to disruption of what is known as tonic inhibition. Instead, they address individual symptoms with a wide variety of medications indicated for other conditions.2,4,15 As a result, they are often ineffective and may be associated with significant side effects:

  • Melatonin is commonly used to aid sleep, but responses vary and efficacy may be lost over time. Other sedatives are sometimes used, although they have not been approved specifically in Angelman syndrome. Because of other broad side effects, they are mostly avoided.2,16,17
  • Long-term anti-seizure medication is used to manage the disease, though patients present with multiple seizure types that are typically refractory to medications.2,18
  • Other medications such as antidepressants may be used to alleviate some symptoms while exacerbating others.2,19

Tonic inhibition and GABA signaling

Angelman syndrome is caused by loss of function of the UBE3A gene, which plays a critical role in neurological communication, resulting in a decline in tonic inhibition.2

A human brain is constantly inundated with sensory information like sights, smells, sounds and touch. Tonic inhibition is the physiological function of the delta (δ)-selective extrasynaptic GABAA receptor that allows the brain to discriminate between sensory information and background network activity, essentially filtering out “white noise” to focus on the important information.36 If tonic inhibition is reduced, the brain is overloaded and loses the ability to distinguish signal from noise.

Tonic inhibition acts in specific regions of the brain that regulate critical functions such as behavior, motor control, sleep and cognition.32-35 Impaired tonic inhibition is believed to be the underlying neurological dysfunction responsible for many of the symptoms in Angelman syndrome.25,28-32

Communications in the brain are governed by chemical signals called neurotransmitters, which can create excitatory and inhibitory signals (such as those required for tonic inhibition). GABA is an essential inhibitory neurotransmitter that helps maintain critical functions through tonic inhibition. In Angelman syndrome, the loss of function of the UBE3A gene disrupts normal function of the cell, leading to reduced GABA levels.25-27 The shortage of GABA cannot maintain tonic signaling, leading to a decline in tonic inhibition.25

Studies in mice have shown that tonic inhibition acts in specific regions of the brain that regulate distinct processes.

 

Recent advances in Angelman syndrome

The National Committee on Vital and Health Statistics recently designated a new and specific ICD-10 code for Angelman syndrome. An ICD code is used to document an individual’s medical condition; the dedicated code for Angelman syndrome is making it easier to conduct research, determine prevalence, recruit for clinical trials, track outcomes and develop protocols for standard of care.
 

References

1. Cabo, R et al. (2017, October). Healthcare and Medical Service Utilization Among Patients With Angelman Syndrome (AS). National Organization for Rare Disorders’ Rare Disease and Orphan Products Breakthrough Summit, Washington, D.C. 2. Buiting K et al. Nat Rev Neurol. 2016;12:584-593. 3. Peters SU et al. Clin Genet. 2004;66:530-536. 4. Wheeler AC et al. Orphanet J Rare Dis. 2017;12:164. 5. ASF Facts about Angelman Syndrome 2009. 6. Bird LM. Appl Clin Genet. 2014;7:93-104. 7. Clayton-Smith J. Dev Med Child Neurol. 2001;43:476-480. 8. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/angelman-syndrome/. Accessed June 14, 2018. 9. Williams 2006 10. Prasad 2018 11. Larson 2015 12. Griffith 2011 13. van den Borne 1999 14. Thomson 2016[PG1] 15. Bi X et al. Expert Opin Ther Targets. 2016;20:601-613. 16. Braam W et al. J Intellect Disabil Res. 2010;54:547-555. 17. Didden R et al. Am J Ment Retard. 2004;109:275-284. 18. ASF Foundation. https://www.angelman.org/what-is-as/medical-information/epilepsy-and-its-treatment-for-providers/. 19. Pelc K et al. Neuropsychiatr Dis Treat. 2008;4:577-584. 20. Pirker 2000.[PG2] 21. Whissell P, et al. Neuropharmacology. 2015;88:24-35. 22. Stell 2003. 23. Reeber 2013. 24. Cope 2005 25. Egawa 2012 26. Lee 2014 27. Roden 2010 28. Bruinsma 2015 29. Ciarlone 2016 30. Judson 2016 31. Winsky 2007 32. Brickley 2012 33. Joshi 2013 34. Glykys 2008 35. Tong 2015[PG3] 36. Duguid I et al. J Neurosci. 2012;32:11132-11143 37. Ovid data on file.