Angelman syndrome is a rare genetic disorder characterized by severe developmental delay, intellectual disability, speech impairment, and problems with balance and coordination. While the condition is present at birth, developmental delay usually becomes noticeable in babies between 6 and 12 months of age. Children with Angelman syndrome often have microcephaly (when the head is smaller than normal), may experience seizures, and typically have a happy demeanor marked by smiling and laughter. Other symptoms and features of the condition tend to appear during childhood after one year of age.

Angelman syndrome is a lifelong condition. People with the condition are usually unable to live independently and need support and care throughout their lives.

It is estimated that the condition occurs in one out of every 12,000 to 20,000 people. It equally affects males and females.

While there is no cure for Angelman syndrome, treatments such as speech, physical, and occupational therapy, as well as anti-seizure medications, can help manage symptoms and improve quality of life.

“New molecular-based treatments, including antisense oligo and gene therapy, are under development,” says Yong-hui Jiang, MD, PhD, chief of Medical Genetics at Yale School of Medicine.

Angelman syndrome is a genetic disorder that affects the nervous system. The condition is named after Harry Angelman, a British pediatric neurologist who first described it in 1965.

People with Angelman syndrome typically have significant developmental delays, meaning that developmental milestones, such as sitting, crawling, and walking, occur later than normal. Voluntary movements, such as walking, may be jerky, stiff, and uncoordinated. People with the condition may also have balance problems and tremors that make walking difficult.

People with the condition also have severe learning disabilities, and most are non-verbal or can speak only a few words. However, they are often able to communicate to some degree through signing, gestures, or with the use of visual aids, such as communication cards or boards. Other common signs and symptoms include frequent laughing and smiling, seizures that typically begin by age 3, and microcephaly, among others.

Some of the signs and symptoms of Angelman syndrome vary by age. Seizures, for example, are often most severe during early childhood, improving over time until they resolve in a person’s teens and early 20s. However, seizures may return in a person’s 20s or 30s. As another example, infants and young children with Angelman syndrome usually have significant sleep problems. In many cases, these sleep problems improve in adulthood, though they often do not go away completely. However, other symptoms, including problems with coordination of voluntary movements and limited or absent speech, typically continue into adulthood.

Angelman syndrome is caused by the loss of function of a gene called UBE3A. This gene is located on chromosome 15 (humans have 46 chromosomes in total). It carries instructions for making a protein thought to play an important role in the development and function of the nervous system. When the UBE3A gene does not work correctly or is absent, the nervous system does not develop or function in a normal way, which can cause Angelman syndrome.

People inherit two copies of most genes, including UBE3A. One copy comes from each parent. Usually, both copies of each gene are active. However, for the UBE3A gene, only one copy—inherited from the individual’s mother (the maternal copy)—is functional. The copy inherited from the father is turned off, or silenced, meaning it is not active. This is known as genomic imprinting (more precisely, the gene inherited from the father is said to be imprinted).

There are four genetic mechanisms that affect the maternal copy of the UBE3A gene or the section of chromosome 15 where the UBE3A gene is located, which can cause Angelman syndrome:

• Deletion of the segment of the maternally inherited chromosome 15, where the maternal copy of UBE3A is located. This accounts for around 70% to 75% of cases of Angelman syndrome. Because the part of the chromosome that contains the maternal copy of UBE3A is deleted, the gene is missing and, therefore, cannot perform its normal function. These are usually sporadic “de novo” deletions, meaning they occur randomly and are not inherited from the parents.
• Certain mutations in the maternal copy of the UBE3A gene, which account for about 10% to 20% of cases.
• Paternal uniparental disomy (UPD) of chromosome 15, which accounts for around 3% to 7% of Angelman syndrome cases. UPD occurs when a person inherits two copies of a chromosome or part of a chromosome from one parent and no copies from the other parent. In this instance, Angelman syndrome occurs when a person inherits two copies of chromosome 15—and therefore two copies of the UBE3A gene—from their father (known as paternal UPD of chromosome 15) and no maternal copy of the chromosome. Because paternal copies of the UBE3A gene are silenced, these two paternal copies of UBE3A are inactive, resulting in Angelman syndrome. Over 99% of cases of paternal UPD of chromosome 15 occur spontaneously and are not inherited.
• Imprinting center defects on chromosome 15, which account for 3% to 5% of cases of Angelman syndrome. The imprinting center determines which genes are imprinted, or turned off. In some cases, a mutation or other problem in the imprinting center of chromosome 15 causes the maternal copy of the UBE3A gene to be turned off and thereby inactive, resulting in Angelman syndrome.

The symptoms and features of Angelman syndrome may vary based on the genetic mechanism that causes the condition.

In rare cases, with a partial genetic deficiency of UBE3A due to mosaic mutations of UBE3A or an imprinting mutation, their presentations are significantly milder.

Angelman syndrome can cause a range of symptoms, including:

• Delayed motor development:
  • Delayed ability to crawl
  • Delayed ability to sit, often until after one year of age
  • Delayed ability to walk, often until age 3 to 5; around 10% of children are never able to walk
• Movement problems:
  • Tremors in the arms and legs
  • Voluntary movements, such as walking, may be jerky, uncoordinated, and clumsy
  • Balance problems
  • Arms held in uplifted position, bent at the elbows with hands waving while walking
• Speech problems:
  • Infants and babies babble and coo less than other infants
  • Speech is entirely absent in most people with Angelman syndrome, though some are able to use a few words
  • Ability to understand language (receptive language ability) is better than the ability to speak
• Microcephaly:
  • About 25% to 80% of children with Angelman syndrome develop microcephaly at age 2 due to delayed or slow growth in head circumference
  • Microcephaly may also affect adults with Angelman syndrome
• Seizures:
  • Usually begin by age 3
  • Occur in over 80% of people with Angelman syndrome
  • Up to 90% of people with the condition have epilepsy
• Sleep problems:
  • Waking up frequently and early
  • Difficulty falling to sleep
  • Reduced need for sleep
• Behavior:
  • Frequent laughter and smiling
  • Happy demeanor
  • Easily excitable, frequently with hand flapping
  • Short attention span
  • Hyperactivity
  • Mouthing or excessive chewing of objects
  • Attraction to and/or fascination with water
• Feeding and gastrointestinal problems:
  • Infants may have difficulty sucking, which can make breast and bottle feeding difficult
  • Decreased muscle tone
  • Gastroesophageal reflux disease (GERD), which affects 45% to 65% of people with Angelman syndrome
  • Constipation
• Other symptoms:
  • Protruding tongue
  • Crossed eyes (strabismus)
  • Wide mouth
  • Widely spaced teeth
  • Flattened back of the head
  • Scoliosis (abnormal sideways curvature of the spine)
  • Obesity (in older children and adults)
  • Paler skin and lighter hair and eye color than other family members
  • Feet spaced widely apart when standing and walking, with pronated ankles (when the foot rolls inward)
    

To diagnose Angelman syndrome, doctors typically review the patient’s medical history, perform a physical exam, and run one or more diagnostic genetic tests. Angelman syndrome is usually diagnosed in early childhood, at about age 2, on average.

The doctor may begin to make a diagnosis by asking whether the child has had any developmental delays and has any signs or symptoms associated with Angelman syndrome, such as limited or absent speech, balance problems, jerky and/or uncoordinated voluntary movements, seizures, sleep problems, and/or frequent laughter and smiling among others.

During a physical exam, the doctor will check for signs and symptoms of Angelman syndrome. They may evaluate the child’s movement, balance, gait, head size, and other indications of the condition.

One or more genetic tests may be performed to confirm the diagnosis. These tests require a blood sample. They may include:

• DNA methylation analysis. This is usually the first test done when Angelman syndrome is suspected. DNA methylation analysis can detect chromosomal deletion, UPD, and imprinting defects. Angelman syndrome is diagnosed if this test detects an abnormality. DNA methylation analysis, however, cannot identify which of these three mechanisms is present. Because of this, additional genetic tests are done to determine the genetic cause of the condition. DNA methylation analysis detects about 80% of people with Angelman syndrome.
• Fluorescent in situ hybridization (FISH) or array-based comparative genomic hybridization (array CGH). These tests, which detect deletions in chromosome 15, are performed if the DNA methylation analysis detects an abnormality. A positive result means there is a deletion in chromosome 15. However, if these tests do not identify a chromosomal deletion, additional tests are necessary to check for UPD or other causes of Angelman syndrome.
• DNA marker analysis for UPD. If a FISH or array CGH test is negative, DNA marker analysis is done to determine whether UPD is present. It can determine if an individual has inherited two copies of chromosome 15 from their father. If the DNA marker test does not show that UPD is present, then it is likely that an imprinting defect is the cause of Angelman syndrome. Additional tests can confirm the presence of an imprinting defect.
• DNA mutation analysis. If the DNA methylation analysis is negative (i.e., no abnormality is detected), but the doctor still suspects Angelman syndrome, a DNA sequencing analysis may be done to determine whether there is a mutation in the UBE3A gene that could cause the condition.

An electroencephalogram (EEG), a test that measures the brain’s electrical activity, may also be performed to help diagnose Angelman syndrome. During an EEG, several electrodes are placed on the patient’s head. The electrodes are connected to a machine that records and displays electrical signals as patterns. People with Angelman syndrome have a characteristic pattern of electrical activity that can aid in diagnosis.

The doctor may also order a magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain to help make the diagnosis. Typically, the brain structure is normal, though the MRI or CT may show mild shrinkage of the cortex or other abnormalities.

There is no cure for Angelman syndrome; however, treatments are available that can help manage symptoms and improve quality of life.

Treatment is tailored to each patient based on their symptoms and needs. Treatments may include:

• Anti-seizure medications (also known as anticonvulsants or anti-epileptic medications), which can help prevent, reduce, and lessen the severity of seizures. Many different anti-seizure medications are available including clobazam, levetiracetam, lamotrigine, and clonazepam, among others.
• Physical and occupational therapy, which can help improve motor skills, such as walking, mobility, and balance. Occupational therapy aims to improve skills involved in daily activities.
• Speech therapy, which is used to manage speech problems. Therapy typically focuses on developing nonverbal communication skills, such as sign language, and using visual communication aids, such as picture cards.
• Behavioral therapy, which may help manage hyperactivity, sleep problems, aggressive or self-injurious behavior, and other behavioral concerns.
• Orthotics including ankle braces or back braces, which may be used to improve walking and for scoliosis treatment, respectively. In some cases, surgery may be necessary to treat scoliosis.
• Good sleep habits and melatonin, which can help improve sleep problems. Good sleep habits may include keeping a consistent sleep schedule and avoiding caffeine before going to sleep. Taking a small dose of melatonin an hour before may also help.
• GERD treatments, which may include lifestyle modifications, medications, and, in some cases, surgery.
• Laxatives and/or a high-fiber diet, which may be used to treat constipation.
• Special nipples and feeding therapy, which may be used to improve feeding in babies with sucking problems.
• Central nervous system stimulants such as methylphenidate, which may be used to treat hyperactivity.

The outlook for people with Angelman syndrome varies based on a number of factors, including the genetic cause of the condition, which symptoms are present, their severity, and timing of and response to treatment. In general, the outlook is best for those who receive an early diagnosis and treatment, including physical, behavioral, and speech therapy.

Angelman syndrome is a lifelong condition, and while those with Angelman syndrome have a nearly normal lifespan, they are generally unable to live independently. Certain symptoms, such as sleep problems, tend to improve in adulthood, though others, such as balance and coordination issues, may persist.

“Physicians of clinical genetics and neurology at Yale Medicine have extensive experience in the diagnosis and management of Angelman syndrome,” says Dr. Jiang. “In addition, investigators at Yale Medicine are conducting clinical trials and/or developing a molecular and gene therapy or correction-based therapies.”