What is Angelman Syndrome?
Angelman Syndrome is a genetic disorder that causes physical, neurological, and developmental symptoms. The condition affects approximately 1 out of every 15,000 people. Babies born with Angelman Syndrome usually appear typical at birth, but the first signs of the disorder appear between 6 and 12 months of age. Neurological and psychological symptoms typically follow developmental delays.
Symptoms of Angelman Syndrome
Common symptoms of the disorder include:
- Early developmental delays, including failures to walk or speak at the typical time
- Intellectual delays and impairment
- Seizures, often beginning at 2 or 3 years of age
- Difficulties with walking and balance
- Stiff or uncoordinated movements
- No speech or minimal speech development
- Sleep disruptions
- Frequent smiling and laughter
- Excitable demeanor
People with Angelman Syndrome sometimes have distinctive physical features, including fair skin, light hair, and eye color.
The symptoms of the disorder are not usually life-threatening. People with the syndrome have, on average, a somewhat shorter than normal life expectancy, but they typically live a long life.
What Causes Angelman Syndrome?
Angleman Syndrome is caused by an abnormality in the UBE3A gene. This gene is responsible for producing an enzyme called ubiquitin protein ligase E3A. This enzyme provides for normal neurological development by controlling the build-up of potentially harmful proteins in the nervous system. When the UBE3A gene is missing or damaged, as is the case in Angelman Syndrome, production of ubiquitin protein ligase is hindered, leading to abnormal neurological development.
The exact causes of Angelman Syndrome are unknown. Sometimes abnormalities with the UBE3A gene can be inherited, and in other cases, damage to the gene seems to occur spontaneously during the early development of the fetus. In about 10% of cases, there is no damage to the UBE3A gene, and the cause of the disorder is unknown.
There are no known factors that increase the risk of the development of the syndrome, and in most cases, there is no family history of the disorder.
Is Angelman Syndrome Hereditary?
Most cases of Angelman Syndrome are not inherited. The disorder results from abnormalities in a child’s genetic material, but the anomalies rarely exist in the parents’ cells. The damage to the UBE3A gene often occurs spontaneously during the early development of sperm or egg cells or during the early development of the embryo after fertilization.
In about 3%-5% of all cases, Angelman Syndrome appears to be inherited. In these cases, an abnormal change in a parent’s UBE3A gene or in another related gene may be passed to the child, and that abnormal gene may cause the disorder to develop. Children with a family history of the condition have a slightly greater chance of having the disorder themselves. However, inherited cases of the syndrome account for only a tiny percentage of all cases.
How Is Angelman Syndrome Detected?
Early detection of Angelman Syndrome is difficult because the disorder’s earliest signs may be similar to other conditions. Developmental delays are often noticeable by six months of age, but these delays may stem from another cause. The symptoms that are more characteristic of Angelman Syndrome don’t begin to show up until later, typically after a child is a year old.
Early signs that could indicate Angelman Syndrome include:
- Developmental delays in movement or balance
- Intellectual developmental delays
- Developmental delays in speech
- Small head size
- Flatness at the back of the head
- Frequent laughter
How Is Angelman Syndrome Diagnosed?
While developmental delays may lead doctors to suspect that Angelman Syndrome may be present, a definitive diagnosis is made via blood tests that look for the specific genetic abnormalities associated with the disorder.
Genetic tests commonly used to diagnose Angelman Syndrome include:
- DNA Methylation Test. This test looks for the specific abnormalities of the UBE3A gene associated with Angelman Syndrome. Most cases of the disorder can be identified with this test.
- Genetic Sequence Analysis. This test can detect abnormal changes in the UBE3A gene that may not be detected by the methylation test.
- Chromosomal Microarray (CMA). This test looks for missing portions of genetic material. CMA can confirm cases of Angelman Syndrome indicated by other tests and identify the exact genetic abnormalities involved. It can also sometimes detect the disorder when other tests are negative.
In about 10% of cases, the symptoms of Angelman Syndrome are present without the known associated genetic abnormalities. In these cases, genetic testing may not definitively diagnose the disorder.
PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.
How Is Angelman Syndrome Treated?
There is no cure for Angelman Syndrome. Treatment programs can help to alleviate symptoms, prevent secondary complications, and improve the effects of symptoms.
Medications or therapies may be prescribed to treat physical symptoms. Symptoms of Angelman Syndrome that may respond to treatment include:
- Gastroesophageal reflux (GERD)
- Strabismus (crossed eyes)
- Feeding problems
Therapies commonly used to treat Angelman Syndrome include:
- Physical therapy to treat walking, balance, and movement problems
- Speech and communication therapies. These therapies may include the use of signing, communicative technologies, or other non-verbal communication methods.
- Occupational therapy
- Behavioral therapies to treat hyperactivity or attention-deficit problems
How Does Angelman Syndrome Progress?
People with Angelman Syndrome are typically in good health apart from the disorder and usually enjoy a normal lifespan. Developmental limitations cause life-long problems with movement and communication, but in many cases, sufferers are able to learn to communicate using non-verbal methods.
Angelman Syndrome is not progressive, and most symptoms do not worsen after childhood. Seizures often improve or cease altogether after adolescence. Sleep disturbances may also improve, although many sufferers experience persistent sleeplessness into adulthood. In adolescence, anxiety and behavioral issues may worsen. Teen sufferers may develop twitching or involuntary jerky movements in their hands, arms, and body.
How Is Angelman Syndrome Prevented?
There is no known way to prevent Angelman Syndrome. Researchers have not identified any factors that increase or decrease the risk of developing the disorder. The genetic abnormalities that trigger the condition usually occur spontaneously from unknown causes. In some cases, scientists have been unable to identify which genes are involved in the development of the disorder.
Angelman Syndrome is, in rare cases, inherited. Those with a family history of the disorder may want to speak with a genetic counselor to assess their risk before becoming pregnant.
Angelman Syndrome Caregiver Tips
Angelman Syndrome is a life-long disorder, and a child who suffers from it will always require care. Caregivers must have the energy and stamina to deal with the condition for years on end, a demanding situation that takes its toll on even the most devoted parents. To help your child and yourself cope effectively, keep these tips in mind:
- Educate yourself about the disorder. Angelman Syndrome is a complex disorder that impacts every sufferer in a unique way. You’ll be better able to understand and meet your child’s needs if you learn about the disorder’s causes and effects. Knowledge will bring peace of mind when you know that you’re doing everything you can to better your child’s life.
- Reach out to the AS community. Angelman Syndrome is rare, and you’re likely to feel as if you and your child are the only people in the world who understand it. However, that’s not true. Support groups and the community of Angelman families can help you realize that you’re not alone.
- Don’t forget about your own needs. Caring for someone with a chronic illness is a direct threat to the health of the caregiver. Caregivers are prone to depression, poor nutrition, sleep disruptions, and many other physical and mental health problems. It’s essential that you step away from your caregiving duties when you can and take care of yourself. Give yourself permission to exercise, pursue your hobbies, or take a nap when you have the chance. You’ll stay healthier, and you’ll be a better caregiver for your child as a result.
Angelman Syndrome Brain Science
The enzyme called ubiquitin protein ligase E3A plays a critical role in brain cells’ development and function. The enzyme is normally produced in the body’s cells. Through a complex chemical process, it helps dispose of protein by-products within the cells. When the enzyme isn’t produced in sufficient amounts, or at all, the accumulating proteins interfere with the function of neurons, the brain’s signal-transmitting cells. In the absence of ubiquitin protein ligase E3A, neurons do not develop properly, and their ability to communicate with other neurons is hampered.
In the normal reproductive process, a child inherits two copies of each gene, one from each parent. A process called imprinting turns specific genes on and off in the child’s cells, making one parent’s gene active and the other parent’s inactive. In some normal brain cells, imprinting switches off the father’s UBE3A gene (the gene responsible for the production of ubiquitin protein ligase E3A) and switches on the mother’s.
Most cases of Angelman Syndrome occur when something goes wrong with the UBE3A gene.
- Gene deletion. Sometimes the mother’s UBE3A is lost during the process of reproduction or embryo development. The gene is then absent from the child’s cells, and ubiquitin protein ligase production is impaired. This problem accounts for about 70% of Angelman Syndrome cases.
- Gene mutation. In this case, the mother’s UBE3A gene is present in the child’s cells, but an abnormal change in the gene interferes with its function. This problem accounts for about 11% of Angelman Syndrome cases.
- Imprinting errors. In this case, the imprinting process doesn’t work correctly, and the mother’s UBE3A gene is switched off along with the father’s. This causes about 6% of Angelman Syndrome cases.
- Paternal Uniparental Disomy (UPD). Sometimes a child inherits two copies of the father’s UBE3A gene and no mother’s copies. When imprinting happens normally, both copies of the father’s UBE3A gene are switched off, and there is no copy of the mother’s gene to be switched on instead. This problem accounts for about 3% of all Angelman Syndrome cases.
In about 10% of cases in which Angelman Syndrome symptoms are present, there is no discernible problem with the UBE3A gene. This suggests that some other, as yet unidentified, gene or genes is likely interfering with the function of ubiquitin protein ligase in these cases.
Angelman Syndrome Research
Title: A Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome
Study Director: Clinical Trials/Hoffmann-La Roche
UCLA Neuropsychiatric Institute
Los Angeles, CA
This is a Phase I, multicenter, non-randomized, adaptive, open-label, multiple ascending, intra-participant, dose-escalation study using IT administration to investigate the safety, tolerability, PK, and PD of RO7248824 in participants with AS.
Two linked sets of dose escalation cohorts are planned based on two different age groups, namely participants with AS aged ≥ 5 to ≤ 12 years in cohorts A1 to A4 (with at least 2 participants ≤ 8 years old in each cohort) and AS participants aged ≥ 1 to ≤ 4 years in cohorts B1 to B5. The two sets of cohorts will be run in parallel, with each cohort A1-A4 preceding and gating the linked cohort B1-B5 (e.g., A1 precedes B1).
Title: An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome (ELARA)
Study Director: Ovid Therapeutics Inc.
Ovid Therapeutics Investigative Site
This open-label study (OV101-18-002) will evaluate the long-term (52 weeks) safety of OV101 in subjects with AS and provide additional OV101 treatment to those subjects who completed Study OV101-15-001 (NCT02996305). Subjects with AS who completed the pharmacokinetic Study OV101-16-001 (NCT03109756) will also be permitted to participate, provided they meet all entry criteria.
This will be an open-label, long-term safety study for evaluating further treatment with OV101 in subjects with AS who have completed previous Ovid studies (OV101-15-001 or OV101-16-001). There will be no placebo treatment. As this study will enroll subjects who have completed previous AS studies for different periods before entering this study, subjects will be required to complete screening and baseline visits before receiving OV101 under this protocol. This study’s secondary objective is to evaluate the long-term efficacy of OV101 treatment assessed by changes in behavior, sleep, and functioning in individuals with AS.
Title: Angelman Syndrome (AS) Biomarker Study
Study Director: Medical Director/Biogen
Rady Children’s Hospital
San Diego, CA
This study’s primary objective is to measure ubiquitin-protein ligase E3A (UBE3A) protein levels in cerebrospinal fluid (CSF) and to evaluate its utility as a biomarker in support of the development of therapies for AS.
Key Inclusion Criteria:
The ability of the participant’s legally authorized representative (LAR) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local privacy regulations
Must have genetically confirmed diagnosis of AS (UBE3A deletion, UBE3A mutation, paternal uniparental disomy, or imprinting center defect) or dup15q syndrome (with number and size of duplications of 15q specified) provided by the Investigator
Must be scheduled for a procedure unrelated to the study that will involve administration of general anesthesia or conscious sedation.