OVERVIEW

What is Angelman Syndrome?

Angelman Syndrome (AS), also known as Happy Puppet Syndrome, is a genetic disorder.

Patients exhibit severe motor impairments, speech delays, developmental delays, episodic limb tremors, distinct facial features (such as a prominent jaw, protruding tongue, and flattened occiput), and often raise their hands with "flapping" movements while displaying unsteady gait.

Due to sucking or swallowing difficulties, feeding is extremely challenging. However, affected children frequently smile, displaying an angelic demeanor, and rarely cry, hence the name Angelman Syndrome.

This condition is a neurogenetic disorder caused by defects in the q11-13 region of chromosome 15. There is currently no cure, and treatment focuses on supportive and symptomatic care. With timely intervention, some patients may live into their 70s or 80s. Without proper management, life expectancy may be limited to 30–50 years, with significantly reduced quality of life.

Is Angelman Syndrome common?

Angelman Syndrome is a rare disease, listed in China's Rare Disease Catalog, with an estimated incidence of about 1 in 15,000.

SYMPTOMS

What are the manifestations of Angelman Syndrome?

Angelman Syndrome can be caused by various genetic defects, and the clinical manifestations vary significantly among patients with different genetic mutations.

Nearly all Angelman Syndrome patients exhibit symptoms such as developmental delay, balance disorders, limb incoordination, tremors in the limbs, and unsteady gait.

They also display happy behaviors like frequent laughter and easy excitement, often accompanied by hand-flapping, dancing, or hyperactivity. Patients experience speech impairments, either being nonverbal or speaking very little, with nonverbal communication skills surpassing verbal abilities. Although they may say "mom" or "dad" by age 1, their language skills show no further progress afterward.

About 80% of Angelman Syndrome patients also exhibit slower head growth. Seizures (clonic convulsions in limbs or only upper limbs, upward eye rolling, loss of consciousness, and foaming at the mouth) often appear before age 3, mostly during sleep, lasting from seconds to minutes, and resolving spontaneously. The frequency ranges from several times a day to a few times a year, with severity decreasing with age but persisting throughout childhood. Characteristic EEG abnormalities may be detected before age 2, unrelated to seizures.

Additionally, 20%–80% of Angelman Syndrome patients may show the following manifestations:

• Flat occiput with a central indentation of about 1 cm × 1 cm;
• Frequent tongue protrusion;
• Difficulty sucking, swallowing disorders, and feeding challenges in infancy;
• Thin upper lip and prominent jaw;
• Wide-spaced teeth;
• Excessive drooling;
• Constant chewing-like mouth movements;
• Strabismus;
• Hypopigmented skin, lighter hair and eye color compared to family members;
• Excessive leg movements;
• Occasionally raising and waving hands while walking, with unsteady steps, or bending arms, especially during walking;
• Heat sensitivity; abnormal sleep patterns;
• Fascination with water or crinkly items (paper or plastic);
• Obesity;
• Scoliosis;
• Constipation, etc.

CAUSES

What causes Angelman Syndrome?

It is related to the deletion or mutation of the UBE3A (ubiquitin protein ligase E3A) gene, located on the q11-13 segment of chromosome 15.

Depending on the specific issue with UBE3A, the causes of Angelman Syndrome are mainly divided into the following 5 types:

1. Maternal UBE3A gene deletion: The q11-13 segment of chromosome 15 inherited from the mother is missing, leading to Angelman Syndrome. This primarily causes speech impairment and developmental delays. About 70% of cases fall into this category.
2. Maternal UBE3A gene mutation: The UBE3A gene inherited from the mother has mutated, resulting in Angelman Syndrome. Around 13% of cases belong to this type. These children typically have the mildest symptoms, the highest IQ development, and sometimes near-normal adaptive abilities. Some may exhibit constant head shaking, body tremors, or limb movements.
3. Maternal UBE3A gene silencing and imprinting defects: Approximately 6% of cases fall into this category. These children also have relatively higher language and cognitive abilities, with some even able to use simple sentences.
4. Paternal uniparental disomy: The child inherits both copies of the q11-13 segment of chromosome 15 from the father (instead of one from each parent). About 3% of cases belong to this type. These children have a lower incidence of epilepsy, slightly better growth and development, and stronger verbal expression.
5. Chromosomal rearrangement: Angelman Syndrome caused by chromosomal rearrangements accounts for less than 1% of cases, with only a handful of reported instances.

Is Angelman Syndrome hereditary?

It can be hereditary.

Couples who have had a child with Angelman Syndrome should undergo genetic testing and counseling before planning another pregnancy to assess the risk of recurrence, which can range from 0% to 100%.

DIAGNOSIS

How is Angelman Syndrome Diagnosed?

To confirm a diagnosis of Angelman syndrome, doctors will carefully review the mother's pregnancy history, the child's birth and developmental milestones, and the child's symptoms. They will also conduct a thorough physical examination and additional tests, such as brain MRI, EEG, and genetic testing.

Genetic testing can identify the specific cause of Angelman syndrome in a child and classify the condition based on genetic characteristics.

TREATMENT

Which department should be consulted for Angelman Syndrome?

Pediatrics, Pediatric Neurology, Pediatric Internal Medicine, etc.

How is Angelman Syndrome treated?

Currently, Angelman Syndrome cannot be cured. However, to improve the child's quality of life, symptomatic and supportive treatments should be actively pursued in collaboration with doctors. These include:

• Anti-epileptic treatment: Most children experience seizures and require anti-epileptic therapy. The treatment principle involves early and combined use of anti-epileptic drugs. For children with frequent seizures, long-term medication may be necessary, even into adulthood.
• Behavioral disorder treatment: Medications are selected based on specific behavioral issues. For example, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine can alleviate anxiety and hyperactive behaviors; minocycline may significantly improve language and social adaptability; melatonin combined with behavioral therapy can reduce disruptive nighttime behaviors.
• Behavioral therapy: Many children exhibit poor social adaptability, frequent inappropriate laughter, hyperactivity, or aggression. Behavioral therapy, conducted 2–3 times weekly, can help guide children on when to laugh and how to control their actions. Given the variety of behavioral issues, personalized, long-term, and sequential treatment plans are essential.
• Augmentative and Alternative Communication (AAC): AAC tools supplement or replace verbal communication. Patients undergo scenario-based training using gestures, phrases, or pictures to express needs, convey information, and build social relationships. Consistent and long-term use of AAC can enhance comprehension, language, motor skills, and cognitive abilities in children with Angelman Syndrome, meeting daily communication needs. For example, "AngelTalk" is an AAC tool that facilitates easier and more effective interaction between affected children and caregivers.
• Molecular targeted therapy: Currently the only potential cure for Angelman Syndrome, though extensive research is still needed before human application.
• Other treatments: These may include eye surgery, dental correction, orthopedic care, physical therapy, rehabilitation, psychological counseling, speech therapy, etc., tailored to the child's specific needs.

DIET & LIFESTYLE

How should children with Angelman syndrome be cared for?

• For infants with feeding difficulties, special nipples can be used. After feeding, the child should be kept in an upright position or given prokinetic medication to avoid gastroesophageal reflux.
• Spend more time with the child, communicate frequently, and understand their inner world.
• Cultivate the child's interests and hobbies, improve their concentration, and help them learn how to manage negative emotions.
• Children are prone to epilepsy, so supervision is necessary during outings or activities to prevent accidents.

How to respond when a child with Angelman syndrome has an epileptic seizure?

Caregivers should know how to handle seizures:

• Move the child to a flat surface and remove sharp or hard objects nearby.
• Loosen the child's collar.
• Turn the child's head to the side (to prevent choking on vomit) and ensure clear breathing.
• Do not force medication or insert objects into the mouth to avoid choking.
• Do not restrain the child's convulsing limbs to prevent injury.

What social assistance is available for children with Angelman syndrome?

In May 2018, China's National Health Commission and four other ministries jointly issued the First List of Rare Diseases, which includes Angelman syndrome. Due to the difficulty and high cost of treatment, rare diseases have attracted significant social attention. Hospitalization costs for rare disease patients can be reimbursed normally, and partial subsidies are available for special medications and outpatient expenses.

Charities, rare disease benefit concerts, and other initiatives bring hope to families affected by rare diseases.

Families facing financial hardship due to medical expenses can apply for medical aid or temporary assistance. Families with disabilities caused by illness or multiple disabilities may receive special subsidies. Applications for temporary assistance should be submitted as a household unit directly to the local township government, community, or subdistrict office.

PREVENTION

Can Angelman Syndrome Be Prevented?

Yes.

• Preconception Period: For couples with a family history of Angelman syndrome or who have previously had a child with the condition, genetic testing and counseling are essential before planning another pregnancy. This helps assess the risk of having another affected child. By examining the parents' chromosomes and genes, geneticists can determine whether they are at low risk (normal genes, no "copying errors") or high risk (one or both parents have genetic abnormalities, "copying errors" exist), aiding in their decision to conceive.
• Pregnancy: If severe intrauterine growth restriction is detected during pregnancy, specialized tests can determine whether the fetus has a genetic disorder, allowing evaluation of whether termination is necessary.
• Postpartum: Regular health and developmental checkups for newborns enable early detection and treatment of Angelman syndrome, preventing more severe complications.