Angelman Syndrome

Angelman syndrome is a rare genetic disorder that primarily affects the nervous system, causing severe developmental delays, intellectual disability, and problems with movement and speech. Despite these challenges, people with this condition often have a remarkably happy demeanor, with frequent smiling and laughter.

Table of contents

• Overview
• How Common Is Angelman Syndrome
• Symptoms and Characteristics
• What Causes Angelman Syndrome
• Diagnosis and Testing
• Treatment and Management
• Life Expectancy and Prognosis

Overview

Angelman syndrome is a complex genetic disorder that occurs when a specific gene stops working properly. This condition was first described in 1965 by Dr. Harry Angelman, a British pediatrician working in England^[6]. The disorder affects how the nervous system develops and functions, leading to a range of physical and developmental challenges^[3].

At birth, babies with Angelman syndrome typically appear normal. The first signs usually become noticeable between 6 and 12 months of age, when developmental delays start to emerge^[1]. Parents may notice that their baby has trouble sitting unsupported or doesn’t make babbling noises like other children their age^[2].

One of the most distinctive features of Angelman syndrome is the cheerful personality that most affected individuals display. Children and adults with this condition often smile and laugh frequently, sometimes with little or no apparent reason. They tend to be excitable and may flap their hands when happy^[4]. While this happy demeanor is endearing, it’s important to understand that it’s a characteristic of the syndrome itself.

AS, Happy Puppet Syndrome (obsolete term)

How Common Is Angelman Syndrome

Angelman syndrome is rare. It affects approximately 1 in 12,000 to 20,000 people worldwide^[3]. According to the Angelman Syndrome Foundation, there are about 500,000 people living with this condition globally^[1]. The syndrome affects males and females equally^[6].

Symptoms and Characteristics

The symptoms of Angelman syndrome vary from person to person and change with age. However, certain features are commonly seen in most individuals with the condition^[5].

Developmental delays are among the earliest signs. Babies may have difficulty feeding in the first months of life, struggling to coordinate sucking and swallowing. Some infants may need to be fed through a feeding tube^[2]. As they grow, children with Angelman syndrome reach developmental milestones much later than other children. They may not sit, crawl, or walk at the expected ages^[3].

Intellectual disability affects all people with Angelman syndrome. Most individuals have severe limitations in learning and understanding. However, they typically understand much more than they can express and can learn to communicate in other ways^[4].

Speech impairment is one of the most pronounced features of the condition. Most people with Angelman syndrome speak very little or not at all. Some may learn to say a few individual words, but they generally cannot form sentences. Despite this challenge, many can communicate effectively using gestures, signs, picture cards, communication boards, or electronic devices^[2].

Movement and balance problems are common. Children often have difficulty walking due to ataxia (problems with balance and coordination). Their movements may be jerky or tremulous, and their legs may be stiff. Some children may walk with their arms held up in the air^[2]. In mild cases, children may start walking around 2 to 3 years of age, while others may not walk until after age 5^[7].

Seizures are very common in Angelman syndrome. About 80 to 90 percent of people with the condition experience seizures, which typically begin between ages 2 and 3^[1]. The seizures are often most severe during early childhood and may improve over time, sometimes resolving in the teens and early twenties, though they can return later^[8].

Behavioral characteristics include frequent laughter and smiling, often with little apparent cause. People with Angelman syndrome are typically easily excitable and may flap their hands when happy or excited. They often have a short attention span and may be hyperactive, especially in childhood^[2]. Many individuals have a particular fascination with water^[2].

Sleep problems are frequent, especially in young children. Many need less sleep than other children their age and may wake frequently during the night. These sleep difficulties often improve somewhat with age but may not disappear completely^[8].

Physical features may include microcephaly (a small head size), which usually becomes noticeable around 2 years of age. The back of the head may appear flat^[2]. Other features can include a wide mouth with widely spaced teeth, a tongue that protrudes, crossed eyes (strabismus), and skin, hair, and eyes that are lighter in color than other family members^[2].

Additional problems may include feeding difficulties, gastroesophageal reflux disorder (when stomach acid flows back into the food pipe), constipation, and scoliosis (curvature of the spine)^[5].

What Causes Angelman Syndrome

Angelman syndrome is caused by problems with a gene called UBE3A. This gene contains instructions for making a protein that plays an important role in how the nervous system develops and works^[3].

Every person normally inherits two copies of the UBE3A gene—one from each parent. In most parts of the body, both copies of this gene are active. However, in certain areas of the brain, only the copy inherited from the mother (the maternal copy) is turned on and working. The copy inherited from the father is naturally silent in these brain regions. This parent-specific pattern is called genomic imprinting^[3].

Angelman syndrome occurs when the maternal copy of the UBE3A gene is missing or not working properly. When this happens, there is no active copy of the gene in certain parts of the brain, which affects how the nervous system functions^[3].

There are several ways the maternal UBE3A gene can be lost or damaged. The most common cause, accounting for about 70 percent of cases, is a deletion—a segment of the maternal chromosome 15 that contains the UBE3A gene is missing^[3]. In about 10 to 20 percent of cases, the maternal copy of the UBE3A gene has a mutation that prevents it from working properly^[3].

In a small percentage of cases, Angelman syndrome results when a person inherits two copies of chromosome 15 from their father instead of one from each parent. This is called paternal uniparental disomy^[3]. Rarely, the syndrome can be caused by other genetic changes that affect how the UBE3A gene is turned on or off^[3].

In most cases of Angelman syndrome, the parents do not have the condition, and the genetic change happens by chance around the time of conception. The disorder is usually not inherited^[2]. In 10 to 15 percent of cases, the cause remains unknown despite genetic testing^[3].

Diagnosis and Testing

A doctor may suspect Angelman syndrome if a child’s development is delayed and they show the distinctive characteristics of the condition, such as frequent laughter, movement problems, and severe speech difficulties^[2]. Most children are diagnosed between the ages of 9 months to 6 years, when physical and behavioral symptoms become apparent^[2].

A blood test is used to confirm the diagnosis. Several different genetic tests will be performed on the blood sample^[2]. These tests look for missing chromosomes or pieces of chromosomes, changes in the UBE3A gene, and patterns that show whether the gene is working properly^[2].

The first test often performed is called a DNA methylation test. This screening test can detect about 85 percent of individuals with Angelman syndrome, including those with a deletion or certain other genetic changes^[14]. If the methylation test results are normal but Angelman syndrome is still suspected, doctors may order a UBE3A gene sequencing test to look for mutations in the gene itself. This can detect an additional 11 percent of cases^[14].

Because seizures are so common in Angelman syndrome, doctors may also perform an electroencephalogram (EEG), which measures the electrical activity of the brain^[9]. However, diagnosing seizures can be challenging because movement abnormalities common in Angelman syndrome can be mistaken for seizures, and EEG abnormalities can exist even when seizures are not present^[14].

It’s important to know the specific genetic change that caused Angelman syndrome in each child. This information helps determine the chance of having another child with the condition^[2].

Treatment and Management

There is currently no cure for Angelman syndrome, and no treatment can address the underlying genetic cause. However, many therapies and interventions can help manage symptoms and improve quality of life^[9].

Seizure management is often necessary. The most commonly used medications for seizures in Angelman syndrome are levetiracetam and benzodiazepines such as clonazepam and clobazam^[14]. It’s important to note that certain anti-seizure medications, including vigabatrin, carbamazepine, and tiagabine, should not be used in people with Angelman syndrome because they can make seizures worse^[14]. For some individuals, a ketogenic diet (high in fat, low in carbohydrates) may help control seizures, particularly when medications are not effective^[19].

Physical therapy can improve posture, balance, and walking ability. It’s also important for preventing permanent stiffening of the joints as people with Angelman syndrome get older^[2]. Some individuals may benefit from braces to help with walking difficulties or back braces to help prevent scoliosis^[19].

Occupational therapy helps develop skills needed for daily activities and can address fine motor challenges^[2].

Speech and communication therapy is essential. While most people with Angelman syndrome will not develop functional speech, they can learn to communicate effectively using other methods. These include sign language, picture cards or communication boards (such as Signalong, Makaton, or PECS), and electronic communication devices including iPad applications and tablets^[2]. Providing multiple ways to communicate can reduce frustration and challenging behaviors^[19].

Behavioral therapy may help address challenging behaviors such as hyperactivity, anxiety, and short attention span. Understanding that difficult behaviors are often a result of frustration with communication can help caregivers respond more effectively^[19].

Sleep problems may be treated with medications such as melatonin or diphenhydramine, or with prescription medications if needed^[19]. Establishing a consistent bedtime routine and creating a comfortable sleeping environment can also help^[19].

Gastrointestinal issues such as constipation can be treated with laxatives, and gastroesophageal reflux can be managed with medications^[19]. Older children and adults with Angelman syndrome tend to gain weight easily, so a healthy diet and regular physical activity are important^[19].

Early intervention services and ongoing educational support are crucial. Most children benefit from starting physical, occupational, and speech therapies early and continuing them as long as they are needed^[4].

Research into new treatments is ongoing. Scientists are exploring ways to reactivate the silent paternal copy of the UBE3A gene and investigating traditional gene therapy approaches^[21]. Clinical trials are testing experimental treatments, and families may wish to discuss participation in research studies with their healthcare providers^[4].

Life Expectancy and Prognosis

People with Angelman syndrome have a near-normal life expectancy^[2]. The condition is not life-threatening, and individuals can live long, happy lives^[1].

However, people with Angelman syndrome will need support throughout their lives. Most are unable to live independently and require lifelong care^[8]. They continue to have intellectual disability, severe speech impairment, and movement challenges as they age^[3].

As people with Angelman syndrome grow older, they often become less hyperactive and excitable. Sleep problems tend to improve, though they may not resolve completely^[3]. Seizures are often most severe during early childhood and may improve over time^[8].

With appropriate support, therapies, and medical care, individuals with Angelman syndrome can participate in many activities and have meaningful relationships with family and friends. Many are social, affectionate, and bring joy to those around them^[7].