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Angelman Syndrome
What is Angelman syndrome?
Angelman syndrome (also called AS) is a rare genetic disorder that affects the normal development of the nervous system of an infant.[1] It is estimated that AS affects approximately 1 in every 23,000 births, and it affects both males and females.[2,3,4] The main cause is a genetic problem with the UBE3A gene, but some children can have problems with additional genes, too.[1,5,6]
The first signs appear in the first year after birth, when the infant has problems growing and developing like the other, typically developing children. Later, other common signs appear, such as difficulties with walking and balancing. Some symptoms improve in older people with AS, and the life expectancy is normal. People living with Angelman syndrome require life-long care, but they can live a happy life.[1,5]
What causes Angelman syndrome?
People’s genetic makeup depends on what they inherit from their parents. Typically, human cells have 23 pairs of chromosomes: one coming from the mother and one from the father. This means that two versions (copies) of each gene are present, one paternal copy and one maternal copy.[5]
In people without Angelman syndrome, the UBE3A gene, which is located on chromosome 15, is turned on (expressed) on the mother’s copy, and is turned off (silenced) on the father’s copy.[1] However, in people with Angelman syndrome, the mother’s copy is missing or malfunctioning, and the father’s copy is turned off. This means that neither copy is creating the UBE3A protein, and the material that the developing brain needs is missing. This leads to problems with developing, controlling speech, movement, learning and sleeping.[1]
There are four different genetic types of Angelman syndrome:[7]
- Deletion: Part of chromosome 15 is deleted, causing the maternal copy of UBE3A and single copies of a few other neighbouring genes important for development to be physically missing (so-called ‘deletion AS’)
- Mutation: Mutations or “typos” in the maternal gene copy, causing the created protein to be different from what is needed
- Uniparental disomy or UPD: The child accidentally inherited both copies of chromosome 15 from the father, meaning both copies of UBE3A are turned off
- Imprinting center defect (ICD): Although the child has one copy of chromosome 15 from each parent, the maternal chromosome 15 behaves like a paternal chromosome 15, and UBE3A is turned off.
What are the symptoms of Angelman syndrome?
Symptoms are different for each child. Some can have symptoms that are more serious, for example a complete lack of speech, while others might be able to speak a few words.[1]
Many children diagnosed with AS:[1,5,7,8]
- Lack cooing or babbling
- Are slower to get to the stage where they can pull themselves up to stand or start crawling
- Are unable to walk without help until the age of 3
- Have seizures, usually beginning before age 3
- Are unable to speak more than a few words
- Move in an unbalanced way and shake while walking (tremor)
- Have sucking/swallowing and feeding problems during infancy
- Have a happy demeanour with frequent laughing and smiling
- Have sleeping problems
- Can be restless (hyperactive)
- Have a short attention span
- Have a fascination for water
- Have curved spine (scoliosis)
Not everyone with these symptoms will have Angelman syndrome. They may be caused by other conditions. But, if your child has any of these symptoms, it is important to get them checked by your doctor.
In general, children with the deleted maternal copy of the UBE3A gene (deletion AS) have the more serious symptoms, and those with two paternal versions have less severity in their symptoms.[9]
Learn more about Angelman syndrome
How is Angelman syndrome diagnosed?
Angelman syndrome shares some common characteristics with other disorders, and this makes the diagnosis harder or leads to misdiagnosis.[7] The first testing can be started in prenatal stage (when the baby is still in the mother’s womb) with a non-invasive test to see normal growth.[1]
After birth, a series of blood tests can help confirm the diagnosis:[1,10,11]
- Methylation test: This test can determine whether the maternal copy of chromosome 15 is present or not, and can identify most AS cases due to deletion, UPD or ICD.
- FISH test (fluorescence in situ hybridization): This test can tell if the maternal UBE3A gene is fully or partially deleted.
- DNA marker test: This test will tell if the cause of AS is two copies of chromosome 15 from the father. If the test is positive, it can confirm UPD as the reason for AS. If the test is negative, the reason might be the mother’s copy that is partially turned off.
- Chromosomal microarray analysis: detects the number of copies of a specific region on the chromosome. This helps to determine any deleted or extra genetic material (can identify deletion AS and determine UPD).
- Whole exome sequencing: This genetic testing is able to detect rare variants of Angelman syndrome, which cannot be seen with other techniques. This test is the only way to find UBE3A mutations.
What treatment options are available for Angelman syndrome?
There are currently no disease-modifying treatments for Angelman syndrome. The management of AS is mostly symptomatic, meaning that slowing or lessening the symptoms of AS is the main goal, such as controlling seizures.[1,8,9]
Children with AS tend to have limited speaking skills, so speech and language therapy with the use of picture cards, sign language or applications on a phone or tablet can improve their non-verbal skills.[1,8,9]
Other options try to manage the additional symptoms of AS. Modification of the diet or medicines can help with constipation and reflux disease.[1] It is common practice to prescribe drugs to help with sleeping issues.[7] Breastfeeding might not be possible, and using special nipples, monitoring weight gain and visiting a specialised team to help with breastfeeding problems is advised.[1] For the developmental delay, early and individualised intervention programs can be organised.[1] Physiotherapy may improve walking ability and balance.[8] Behavioural therapy may help with overcoming hyperactivity or short attention span.[8]
What is the outlook for a person with Angelman syndrome?
Finding a treatment for a disease is a huge, complex task for researchers. Knowing the cause of a disease, however, helps researchers focus on one specific target. Since there is a copy of UBE3A gene from the father, which is turned off, researchers have been trying to find a way to turn on the paternal gene for the treatment of Angelman syndrome.
Multiple clinical trials are running in young children,[12] adolescents[13] and adults[14] with Angelman syndrome, and in healthy adults[15] that could bring the solution one step closer.
If you would like to know more about Roche sponsored clinical trials or are interested in taking part in a clinical trial, speak to your doctor or visit the Roche ForPatients clinical trials page link.
References and further resources
1. Madaan M, Mendez MD. Angelman Syndrome. Accessed 28 November 2022. Available from: Link
2. Mertz LGB, Christensen R, Vogel I et al. Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A. 2013 Sep;161A(9):2197–2203. Available from: Link
3. Luk HM and Lo IFM. Angelman syndrome in Hong Kong Chinese: a 20 years’ experience. Eur J Med Genet. 2016 Jun;59(6–7):315–319. Available from: Link
4. Yakoreva M, Kahre T, Žordania R et al. A retrospective analysis of the prevalence of imprinting disorders in Estonia from 1998 to 2016. Eur J Hum Genet. 2019 Nov;27(11):1649–1658. Available from: Link
5. Angelman Syndrome Foundation. What is Angelman syndrome. Accessed 28 November 2022. Available from: Link
6. Keute M, Miller MT, Krishnan ML et al. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021 Jul;26(7):3625–3633. Available from: Link
7. Maranga C, Fernandes TG, Bekman E et al. Angelman syndrome: a journey through the brain. FEBS J. 2020 Jun;287(11):2154–2175. Available from: Link
8. NHS. Angelman syndrome. Accessed 28 November 2022. Available from: Link
9. Margolis SS, Sell GL, Zbinden MA et al. Angelman syndrome. Neurotherapeutics. 2015 Jul;12(3):641–650. Available from: Link
10. Angelman Syndrome Foundation. Testing and Diagnosis. Accessed 28 November 2022. Available from: Link
11. Triono A, Iskandar K, Nugrahanto AP et al. The role of whole exome sequencing in the UBE3A point mutation of Angelman syndrome: a case report. Ann Med Surg (Lond). 2021 Dec;73:103170. Available from: Link
12. Roche. ForPatients by Roche. A study to investigate the safety of RO7248824 in children with Angelman syndrome and to understand the way the body processes the investigational therapy. Accessed 28 November 2022. Available from: Link
13. Roche. ForPatients by Roche. Study to investigate the pharmacokinetics and safety and to provide proof of mechanism of alogabat in children and adolescents aged 5-17 years with Angelman syndrome (as) with deletion genotype. Accessed 28 November 2022. Available from: Link
14. ClinicalTrials.gov. HALOS: A safety, tolerability, pharmacokinetics and pharmacodynamics study of multiple ascending doses of ION582 in participants with Angelman syndrome. Accessed 30 January 2023. Available from: Link
15. Roche. ForPatients by Roche. A study to assess distribution of RO7248824 in the central nervous system following single intrathecal doses of [89zr] labeled RO7248824 in healthy male participants. Accessed 28 November 2022. Available from: Link
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