What is Angelman Syndrome?
In 1965, a British doctor named Harry Angelman noticed a group of children, he referred to as “Puppet Children,” with similar symptoms. Those children had learning difficulties, struggled with talking or didn’t talk at all, moved in a jerky, unsteady way, but had cheerful and sociable personalities. Eventually, this condition became known as Angelman Syndrome (AS).
Angelman Syndrome is a rare disorder that affects the nervous system. In simple terms, it’s an example of what we call genomic imprinting. In genomic imprinting, the behavior of certain genes depends on whether they were inherited from the mother or the father. Symptoms of Angelman Syndrome include intellectual and developmental challenges, unusual movement that may resemble a puppet’s, sleep issues, and hyperactivity.
Scientists discovered one of the causes of Angelman Syndrome in 1987. Using advanced chromosome inspection techniques, they found that patients with AS had tiny missing parts on a particular region of chromosome 15 (15q11-13). However, later studies found several other ways that this chromosome region could cause AS. Today, we believe the main cause of Angelman syndrome is an issue with a gene called UBE3A in the brain that’s usually inherited from the mother.
What Causes Angelman Syndrome?
Angelman syndrome (AS) is a disorder that is brought about when the UBE3A gene, which is located on the chromosome obtained from the patient’s mother, is not working as it normally should. In addition to this, the same gene on the father’s chromosome is turned off, or “silenced”, in brain cells. The UBE3A gene usually works in a particular way depending on whether it comes from your mother or father. Your brain mainly uses the mother’s UBE3A gene.
Angelman syndrome typically comes about because of a new, unexpected mutation in the UBE3A gene on the mother’s 15th pair of chromosomes. This happens in about 70 to 75% of cases. In a few rare instances (2 to 3% cases), it can happen due to two copies of the father’s 15th chromosome (rather than one from each parent) being present. Additionally, it can occur because of a single gene mutation or a defect in a certain region of the chromosome (around 3 to 10% cases).
In some cases, the syndrome can be inherited if there is a mutation in the UBE3A gene from the mother’s side, or due to a rare subtype of genetic defects called submicroscopic deletion of the imprinting center.
Risk Factors and Frequency for Angelman Syndrome
Angelman syndrome (AS) affects roughly 1 in 20,000 to 1 in 12,000 newborns. It doesn’t favor one gender over the other, affecting both boys and girls equally. However, the actual numbers might be higher since some cases may not be reported or might be misdiagnosed.
Signs and Symptoms of Angelman Syndrome
Angelman Syndrome is a condition that impacts various aspects of learning, behavior, and physical health. The most common signs include problems with movement and balance, limited speech, delayed mental and physical development, uncontrolled laughter and hand movements, and seizures.
Delayed mental and physical development can often be spotted by the time a child is six months old. Some children with Angelman Syndrome may not begin to walk until they’re three years old, while others may need to use a wheelchair. They often walk on their toes and make jerky arm movements. Many display a happy demeanor, frequently laughing and flapping their hands. They are easily distracted and become excited easily, leading to difficulty in concentrating.
By age three, about 80% of children with Angelman Syndrome may experience seizures. This is sometimes accompanied by abnormal brain wave patterns, even when the child isn’t having a seizure. As they grow older, their seizures may lessen during puberty, but often reappear during adulthood.
Many individuals with Angelman Syndrome might also have sleep problems, which could lead to waking up frequently during the night. Their condition usually becomes better as they grow older. The hyperactivity decreases owing to increased muscle rigidity, sleep improves, and concentration gets better. Some may develop obesity in adulthood.
In addition to these, there might be:
- A protruding tongue
- Mouth thrusting and swallowing disorders
- Feeding issues as a baby
- Decreased muscle tone in the torso
- An unusually large jaw
- A wide mouth and widely spaced teeth
- Frequent drooling
- Excessive chewing behavior
- Crossed eyes
- Light skin, hair, and eye color compared to their family (only for a certain type of Angelman syndrome)
- Hyperactive lower limb reflexes
- A wide-set gait with pronated or valgus-positioned ankles
- Arms uplifted and flexed, especially while walking
- Increased sensitivity to heat
- Attraction to water
- Unusual behaviors related to food
- Excessive weight (during childhood)
- Scoliosis (a sideways curve of the spine)
Testing for Angelman Syndrome
Testing for Angelman syndrome, a genetic disorder that primarily affects the nervous system, can begin even before a baby is born. When a fetus shows signs of growth restriction, doctors can use a method known as noninvasive prenatal testing (or NIPS) to check for this condition. This technique has proven to be highly accurate in diagnosing Angelman syndrome while the baby is still in the womb.
If there is suspicion of Angelman syndrome after the baby is born, the next step is to conduct methylation studies. In this test, doctors examine a specific region of the SNRPN gene. Normally, each person has two versions of this region- one from the mother and one from the father. The version from the father is usually “unmethylated” and the version from the mother is “methylated”. But in around 80% of babies with Angelman syndrome, the methylated version from the mother can’t be found.
If the methylation studies don’t give a definitive result, doctors then use a technique called Fluorescence In Situ Hybridization or FISH. This test can spot any missing pieces of chromosome 15 from the mother, which could be causing the syndrome. If the results are negative, they would then check for other possibilities like imprinting defects or paternal disomy- a condition where both versions of chromosome 15 come from the father. These can be confirmed by additional tests on the baby’s DNA.
In cases where the methylation test is negative but there is still a strong suspicion of Angelman syndrome, DNA sequencing can be performed. This test can identify any mutations in the UBE3A gene that may have been missed in the methylation studies. If this test is negative, doctors would then consider other potential diagnoses.
An electroencephalogram (EEG), which measures brain activity, can also be helpful for diagnosing Angelman syndrome as it can show unique patterns associated with the condition. Additionally, it can reveal signs of epileptic activity, which is often present in individuals with Angelman syndrome.
Sometimes, a sleep study (also known as polysomnography) may also be recommended to check for any sleep disorders, which are common in children with Angelman syndrome.
Treatment Options for Angelman Syndrome
Angelman syndrome (AS), a rare genetic disorder, currently has no cure. However, there are various ways to manage its symptoms. Though these approaches may not eliminate AS, they can greatly improve the quality of life for those living with the condition.
If a child with AS has Feeding Problems, there are several measures to support them. For instance, they might have trouble sucking, making breastfeeding hard. In such cases, special bottle nipples can be used. Regular weight check-ups and a referral to a specialized team could also be beneficial for advice on feeding.
If the child suffers from gastroesophageal reflux, a condition causing stomach acids to back up into the esophagus, certain medications such as magnesium carbonate and aluminum hydroxide can be administered to help manage it.
Children with AS often struggle with constipation. Parents can increase their child’s fluid intake, and introduce foods high in fiber or mild laxatives into their diet.
If obesity becomes an issue, regular weight and Body Mass Index (BMI) check-ups as well as regular exercise can help manage it. Some children may also do well on a ketogenic diet, which is a diet high in fats and low in carbohydrates.
Angelman Syndrome often results in Developmental Delays. This potentially includes both growth delays and fine motor skill delays – such as the ability to grasp objects. Physiotherapy, orthotics, and occupational therapy can support children as they learn these skills.
Speech may also be affected in those with AS – speech and language therapy helps children learn both verbal and nonverbal communication methods.
Seizures are a common symptom of AS. Several medications, including sodium valproate, clonazepam, and phenobarbital, are often effective for controlling seizures.
Children with AS may experience Sleep Problems. To address this, doctors recommend following healthy sleep routines and may suggest medication such as melatonin, a hormone that helps control the body’s sleep-wake cycle.
For Vision Problems, regular eye exams are important, as they can help identify issues like strabismus, a condition that causes the eyes to misalign. If detected, a referral to an ophthalmologist should be made.
Someday, there may be New Therapies to treat AS. At the moment, researchers are exploring ways to unsilence the non-working gene in AS. This process might help the body produce a protein that’s lacking in AS. Antisense oligonucleotides(ASO), which work by degrading a specific type of RNA, are also showing promise in early studies. Overall, while treatments for AS are currently focused on managing symptoms, there’s a lot of ongoing research into more targeted therapies.
What else can Angelman Syndrome be?
When doctors are trying to diagnose Angelman syndrome, they need to make sure they’re not mistaking it with other conditions that present similar features. Some of these include:
- Microdeletion Syndromes:
- Phelan–McDermid syndrome (also known as 22q13.3 deletion)
- MBD5 haploinsufficiency syndrome (or 2q23.1 deletion)
- KANSL1 haploinsufficiency syndrome (also called 17q21.31 deletion)
- Single Gene Disorders:
- Pitt–Hopkins syndrome (caused by TCF4 haploinsufficiency)
- Christianson syndrome (caused by SLC9A6 mutation)
- Mowat–Wilson syndrome (caused by ZEB2 haploinsufficiency)
- Rett syndrome (caused by MECP2 mutations)
- Kleefstra syndrome (related to EHMT1)
These conditions and Angelman syndrome have a lot in common, so it’s crucial that physicians conduct thorough tests to ensure they’re making the right diagnosis.
What to expect with Angelman Syndrome
People with Angelman syndrome (AS), a genetic disorder, will experience some level of developmental delay and difficulty with speech and movement. The severity of these symptoms can vary greatly from person to person. This is determined by factors like the specific genetic cause of AS (with larger genetic deletions often leading to more severe symptoms), when the diagnosis was made, and what treatments were given.
Despite these challenges, some people with AS can achieve a high level of movement, speech, and independence in taking care of their day-to-day needs. Most individuals with AS can expect to live a normal lifespan and, with the right care and support, can even improve some of their self-care skills. But, it is key to note that many will require consistent care and attention due to potentially risky behavior.
Early diagnosis and treatments like speech, physical and occupational therapy can greatly improve the person’s quality of life. Symptoms of AS can change as a person ages: seizures and hyperactivity may decrease, and sleep might improve. However, weight gain might become an issue, which can lead to a sideways curvature of the spine, known as scoliosis, and reduce mobility. The onset of puberty and sexual development usually happens normally in patients with AS.
Possible Complications When Diagnosed with Angelman Syndrome
In individuals with Angelman syndrome (AS), a medical condition that comes with its set of related health problems, the main complications generally arise from the associated disorders. One of the issues is that a patient can get injured during seizure or clumsiness episodes due to their condition. AS patients often have hyperactivity, a habit of exploring and intellectual disability, all of which increase the risk of accidents. Accidents significantly contribute to increased illness and risk of death in people with AS.
It’s estimated that between 20 to 80% of AS individuals have troubles with feeding. Depending on how severely malnourished they are, they may need an evaluation of their nutrition or even surgical help, such as inserting a nasogastric tube into their stomach through the nose. Delays in development are commonly observed in these patients. The extent of impairments varies, but most people with AS will require assistance for personal care.
Common Challenges Faced by Angelman Syndrome Patients:
- Injuries from seizures or ataxia (clumsiness)
- Increased risk of accidents due to hyperactivity, exploratory behavior, and intellectual disability
- Feeding difficulties, which may require evaluation of nutrition or even surgical intervention
- Developmental delay, with most patients needing help in their daily care
Preventing Angelman Syndrome
Angelman syndrome (AS) is a condition that, unfortunately, doesn’t have a cure. However, we can manage the symptoms effectively by working with a team of different health professionals. Early diagnosis and consistent treatment, involving speech therapy, physical therapy, and occupational therapy, have been known to improve the individual’s situation.
It’s essential that parents understand that their child with Angelman syndrome will need continuous care and support. This includes regular therapy sessions starting at an early age. The family can also take advantage of genetic counseling. This service is beneficial for those who have AS in their family, as most cases of AS occur randomly, some are inherited. Genetic counseling can help families understand the risk of the syndrome occurring in future pregnancies.
