First described in 1965,[1] Angelman syndrome is a rare genetic disorder affecting roughly 500,000 people worldwide. Patients with Angelman syndrome generally experience developmental delays, intellectual disabilities, extensive speech impairment, issues with movement and balance, epilepsy, and abnormal sleep-wake.[2] Individuals with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements.[2]

Angelman Syndrome Overview

 

Many of the characteristic features of Angelman syndrome result from the loss of function of a gene called UBE3A,[3] located on chromosome 15. UBE3A gene provides instructions for making a protein called ubiquitin protein ligase E3A. Studies suggest that ubiquitin protein ligase E3A plays a critical role in the normal development and function of the nervous system. Both copies of UBE3A are active in several areas of the body; however, the brain has only one activated copy of the gene, which is inherited by the mother. If this copy of the gene is randomly deleted or mutated, the body cannot call upon the father’s contributed UBE3A in this area of the brain to take its place. When this happens, the signs of Angelman syndrome will emerge.[3] In very rare cases (1%), an infant with Angelman syndrome can inherit both chromosome 15 copies by the father, meaning that the mother’s copy is absent and yielding the same result.

According to the latest research, the problem is most commonly the result of a deleted segment on chromosome 15.[1] The deletion or mutation often occurs during germ cell production or during development of the early embryo.[3] In approximately 10% of patients, the patient has both copies of the gene, and the cause of the disorder cannot be determined.[1] In those patients, scientists believe that a combination of other mutations or chromosomal deletions may occur, which culminate in the same effect.

The missing gene activity is critical to regulation of the neurotransmitter GABA. Low postsynaptic concentrations of GABA results in inadequate tonic inhibition.[4]

The prevalence of Angelman syndrome is between 1 in 12,000 and 1 in 20,000 individuals. This means more than 20,000 Americans are affected by the disorder; males and females seem equally affected.[1]

 
PATHOPHYSIOLOGY AND EPIDEMIOLOGY

Many of the characteristic features of Angelman syndrome result from the loss of function of a gene called UBE3A,[3] located on chromosome 15. UBE3A gene provides instructions for making a protein called ubiquitin protein ligase E3A. Studies suggest that ubiquitin protein ligase E3A plays a critical role in the normal development and function of the nervous system. Both copies of UBE3A are active in several areas of the body; however, the brain has only one activated copy of the gene, which is inherited by the mother. If this copy of the gene is randomly deleted or mutated, the body cannot call upon the father’s contributed UBE3A in this area of the brain to take its place. When this happens, the signs of Angelman syndrome will emerge.[3] In very rare cases (1%), an infant with Angelman syndrome can inherit both chromosome 15 copies by the father, meaning that the mother’s copy is absent and yielding the same result.

According to research, the problem is most commonly the result of a deleted segment on chromosome 15.[1] As a result, it is highly unusual to observe an inherited case of Angelman syndrome. The deletion or mutation often occurs during germ cell production or during development of the early embryo.[3] In approximately 10% of patients, the patient has both copies of the gene, and the cause of the disorder cannot be determined.[1] In those patients, scientists believe that a combination of other mutations or chromosomal deletions may occur, which culminate in the same effect.

The missing gene activity is critical to regulation of the neurotransmitter GABA. Low concentrations of GABA postsynaptically results in inadequate tonic inhibition.[4]

The prevalence of Angelman syndrome is between 1 in 12,000 and 1 in 20,000 individuals. This means more than 20,000 Americans are affected by the disorder; males and females seem equally affected.[1]

Angelman Syndrome Explained

SIGNS AND SYMPTOMS

Perhaps the first sign of the disorder in infants is movement disorders and lack of coordination. The poor tonic inhibition manifests in a “jerky” limb action and, in some patients, tremors. The movement disorders are usually apparent between six and 12 months of age. All young children with Angelman syndrome experience significant development delays, affecting speech and learning, causing most to have very limited verbal communication.[1,3]

Path to Diagnosis

 

Children with Angelman syndrome exhibit unusually happy behavior, with bouts of uncontrolled laughter. They are often hyperactive and excitable. Children with Angelman syndrome also exhibit sleep problems, particularly abnormal nighttime duration and night-walking, usually starting in early infancy. Many (but not all) patients with Angelman syndrome are prone to seizures, starting between one and five years of age, which then decrease once the child reaches 12 years.[2,3]

Other signs vary quite a bit from one patient to another. In some milder cases, patients will learn to walk by their third year. Others only begin to walk between five and 10 years of age.[1] A common finding in children with Angelman syndrome is a specific positioning of their arms and hands when walking or excited: This involves keeping their arms up, with the wrists and elbows bent, while flapping their hands. Trunk hypotonia and hypertonia of the arms and legs are also common to these patients.[3]

An important but nonspecific physical sign of Angelman syndrome is microcephaly or small head circumference compared with healthy children of the same age and weight. Some children with Angelman syndrome demonstrate a characteristic facial pattern with the following: an abnormally wide mouth, deeply set eyes, strong chin, and a short and broad skull.[1]

Additional symptoms, which are variable and seen less frequently than those above, include gastrointestinal problems (gastroesophageal reflux or constipation), swallowing and feeding problems in infancy, hypopigmentation of the skin, photophobia, strabismus (crossing of the eyes), and sleep disturbances. As children with Angelman syndrome age, scoliosis and keratoconus have been reported to develop.[1,3]

MANAGEMENT AND CURRENT TREATMENT

Angelman syndrome can be diagnosed through a comprehensive physical examination and patient history. The diagnosis can typically be confirmation with specialized blood testing and chromosome analysis (e.g., DNA methylation studies or microarray chromosome analysis).[1]

Since there is not an FDA-approved treatment to replace the activity of the UBE3A gene, almost all care is supportive or to treat individual symptoms of Angelman syndrome. For example, antiepileptics are used to address any seizures that arise.[3] As mentioned above, sleep disorders are common, and behavioral therapy and sedatives can be helpful in alleviating this problem. Gastroesophageal reflux can be addressed both medically and surgically. Braces and supports are helpful in addressing the onset of scoliosis. Special social support, including vocational services, speech therapy, and physical therapy, can be of assistance in this patient population.

Interestingly, children and adults with Angelman syndrome are not at greater risk of infection, autoimmune disorders, or other specific illness. Standard vaccinations and pediatric care should be undertaken after consulting your primary physician.[1]

The lifespan of patients with Angelman syndrome is not significantly different than the general population, and alternative living arrangements, like group homes, may well be needed to care for these patients over the long term.[1]

The National Organization for Rare Disorders recommends genetic counseling for the families of patients with Angelman syndrome.[1]

FUTURE THERAPEUTIC DIRECTIONS

​Although no approved therapy exists to treat Angelman syndrome, new avenues of research are advancing to directly address the cause of the disorder.[4] A Phase 2 trial of a drug that seeks to increase production of GABA, thereby compensating for the loss of GABA transmission across of neuronal synapse, has demonstrated encouraging results (almost three-quarters of patients experienced clinical meaningful improvement in multiple areas of function.[5] This drug, gaboxadol (OV-101), is currently the subject of a Phase 3 study.[6]

Another novel mechanism involves countering the way in which the paternal copy of the UBE3A gene is turned off. This agent, GTX-102, has begun a Phase 1/2 clinical trial, which is due to be completed in 2022.[7]

Several other research pathways are being explored; however, these are being tested in experimental animal models or are still theoretical. For example, a process using CRISPR epigenome editing may be able to counter silencing of the paternal UBE3Agene.[9] Researchers are also investigating in a mouse model whether use of D-JNKI1-inhibitor peptide can alter signaling activation postsynaptically and lessen the cognitive deficits in patients with Angelman’s syndrome.[8]

CLINICAL TRIAL INFORMATION

A check of www.clinicaltrials.gov in April 2020 revealed seven studies actively recruiting patients with Angelman syndrome. These studies included direct treatment of the disorder as well as symptomatic care.

RESOURCES

National Organization for Rare Disorders (NORD)
Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.

Angelman Syndrome Foundation (ASF)
The mission of the Angelman Syndrome Foundation is to advance the awareness and treatment of Angelman syndrome through education and information, research, and support for individuals with Angelman syndrome, their families and other concerned parties. 

The Mighty
The Mighty is a digital health community created to empower and connect people facing health challenges and disabilities.

Foundation for Angelman Syndrome Therapeutics (FAST)
FAST is run by an all-volunteer board of Angelman syndrome (AS) parents and professionals dedicated to finding a cure for AS and related disorders through the funding of an aggressive research agenda.

Angelman Syndrome News
Angelman Syndrome News  is a news and information website about the disease.

Ovid Therapeutics’ YouTube Channel
Ovid Therapeutics’ channel focused on Angelman Syndrome.

Bold Medicines
Podcast focused on Ovid Therapeutics and Angelman Syndrome.

EURODIS
A non-governmental patient-driven alliance of patient organizations representing 724 rare disease patient organizations in 64 countries. 

Ovid Therapeutics
Ovid Therapeutics is developing lifechanging therapies based on deep understanding of key biological pathways and their central role in rare neurological diseases. 

REFERENCES
  1. Angelman syndrome. National Organization for Rare Disorders 2018. https://rarediseases.org/rare-diseases/angelman-syndrome/. Accessed April 13, 2020.
  2. Maranga C, Fernandes TG, Bekman E, da Rocha ST. Angelman syndrome: A journey through the brain. FEBS J. 2020 Feb 22, 2020 [Epub ahead of print] doi: 10.1111/febs.15258.
  3. Angelman syndrome. NIH Genetic and Rare Disorders Information Center March 31, 2016. https://rarediseases.info.nih.gov/diseases/5810/angelman-syndrome. Accessed April 13, 2020.
  4. Rotaru DC, Mientjes EJ, Elgersma Y. Angelman syndrome: From mouse models to therapy. Neuroscience.Feb 21, 2020 [Epub ahead of print] doi: 10.1016/j.neuroscience.2020.02.017.
  5. Ovid Therapeutics presents additional data and analyses from the Phase 2 STARS clinical trial with OV101 for the treatment of Angelman syndrome at the 65th AACAP annual meeting (press release). Ovid Therapeutics October 25, 2018. https://investors.ovidrx.com/news-releases/news-release-details/ovid-therapeutics-presents-additional-data-and-analyses-phase-2. Accessed April 15, 2020.
  6. A study of OV101 in individuals with Angelman syndrome (AS) (NEPTUNE). ClinicalTrials.gov March 19, 2020. https://www.clinicaltrials.gov/ct2/show/NCT04106557?cond=Angelman+syndrome&draw=3&rank=12. Accessed April 15, 2020.
  7. GeneTx announces IRB approval to begin clinical study of GTX-102 for the treatment of Angelman syndrome (press release). GeneTx February 14, 2020. https://www.biospace.com/article/releases/genetx-announces-irb-approval-to-begin-clinical-study-of-gtx-102-for-the-treatment-of-angelman-syndrome/. Accessed April 15, 2020.
  8. JNK signaling activation in the Ube3a maternal deficient mouse model: its specific inhibition prevents post-synaptic protein-enriched fraction alterations and cognitive deficits in Angelman Syndrome model. Neurobiol Dis. 2020 Feb 19;140:104812. doi: 10.1016/j.nbd.2020.104812. [Epub ahead of print] https://www.mdpi.com/2073-4409/9/4/993/htm
Angelman Syndrome Symptoms

 

Patient Journey With Angelman Syndrome

 

Angelman Syndrome Clinical Studies

 

 

This Angelman Syndrome Learning Page is supported by Ovid Therapeutics. This content was developed by or at the request of CheckRare consistent with the editorial themes provided by the publisher.