ANGELMAN SYNDROME: CAUSES, SYMPTOMS, COMPLICATIONS, TREATMENT AND LATEST RESEARCH

Medically Reviewed by Dr. Sony Sherpa (MBBS)

Angelman Syndrome (AS) is a rare genetic disorder that primarily affects neurological development, characterized by developmental delays, intellectual disability, speech impairment, and movement difficulties. Individuals with AS often exhibit a happy and excitable demeanor, frequent smiling and laughter, and characteristic hand-flapping movements. Due to these features, AS was historically referred to as "happy puppet syndrome”, though this term is now outdated.

Angelman Syndrome affects an estimated 1 in 12,000 to 20,000 people worldwide, making it a rare condition. It was first described by British pediatrician Harry Angelman in 1965 after he observed children with similar developmental patterns.

Causes of Angelman Syndrome

Angelman Syndrome is a neurogenetic disorder caused by abnormalities in chromosome 15, specifically involving the UBE3A gene. This gene is essential in brain development and function. People with Angelman syndrome have a missing or non-functioning maternal copy of the UBE3A gene, which causes the characteristic symptoms of the disorder.

Is Angelman Syndrome Monogenic?

AS is a monogenic disorder, meaning it results from alterations in a single gene—UBE3A. However, different genetic mechanisms can lead to AS, each affecting the gene in distinct ways.

Genetic Mechanisms Behind Angelman Syndrome

There are several genetic causes of AS, including:

• Deletion of the Maternal UBE3A Gene (70% of cases) – The most common cause, when a segment of chromosome 15 containing UBE3A is missing.
• Uniparental Disomy (UPD) (2–3%) – The child inherits two copies of chromosome 15 from the father and none from the mother, leading to the absence of a functional maternal UBE3A gene.
• Imprinting Defects (2–3%) – The maternal chromosome 15 is present, but it carries a defect in the imprinting process, preventing the UBE3A gene from being expressed.
• Point Mutations in UBE3A (5–10%) – Mutations within the gene itself can lead to dysfunction despite the gene being present.
• Unknown or Rare Causes (5–10%) – Some cases do not fit into the above categories, and research is ongoing to understand additional genetic contributors.

Assisted Reproductive Technology (ART) and Angelman Syndrome

Research suggests that assisted reproductive technology (ART) may be linked to a slightly increased risk of rare genetic conditions like AS. This condition is related to how genes are "marked" or tagged in the body, a process called methylation. This tagging is especially important in early development. Fertility treatments might interfere with this tagging process. However, the reason why this happens is still under research, including which ART methods might increase the risk.

Another research suggests that fertility problems and imprinting defects may share the same cause. It also indicates that using hormone treatments to stimulate egg production (superovulation) might increase the risk of imprinting defects in a baby more than the use of ICSI, a common fertility treatment where a single sperm is injected into an egg cell.

However, it is important to note that the overall risk remains low, and more research is needed to clarify whether ART directly increases AS risk or if underlying genetic or epigenetic factors play a role.

Symptoms of Angelman Syndrome

Symptoms of Angelman Syndrome typically become noticeable between 6 to 12 months of age, often when developmental delays, such as difficulty sitting or babbling, become apparent.

When Should You See a Doctor

Since AS affects multiple aspects of growth and neurological function, parents and caregivers should seek medical advice if a child exhibits:

• Unexplained feeding difficulties in infancy.
• Significant delays in motor skills, speech, or cognitive development.
• An unusually happy demeanor with frequent laughter and hand-flapping.
• Seizures or abnormal movements.

Early diagnosis allows for better intervention and support strategies.

Angelman Syndrome Facial Features

Individuals with AS often have distinct facial characteristics, including:

• A wide, smiling mouth with prominent teeth.
• Spaced-out teeth and possible dental issues, such as excessive drooling or teeth grinding (bruxism).
• A small head size (microcephaly) compared to age-matched peers.
• Deep-set eyes and a flat occiput (back of the head).
• Hypopigmentation, leading to light-colored hair, skin, and eyes, especially in those with chromosome 15 deletions.

Developmental Delays

Children with AS experience significant delays in reaching developmental milestones:

• Sitting – Often delayed beyond the expected 6–9 months.
• Walking – Many children do not walk until age 3–4 years, and some may never walk independently.
• Talking – Most people have severely limited speech or may remain nonverbal throughout life.

Intellectual Disability

AS often involves severe to profound intellectual disability, affecting:

• Learning ability – They struggle with problem-solving but often respond well to structured routines and visual learning methods.
• Attention span – Many exhibit short attention spans, hyperactivity, and impulsivity, which may resemble symptoms of ADHD.

Speech Impairment

Most people with AS do not develop functional speech and may rely on alternative communication methods such as:

• Sign language or gestures
• Augmentative and Alternative Communication (AAC) devices, including speech-generating devices and picture boards

Despite speech difficulties, they often have strong social engagement skills and can understand more than they can express.

Movement Difficulties

AS is associated with ataxia (lack of coordination) and tremors, making voluntary movements difficult. Additional motor issues include:

• Jerky, stiff, or exaggerated movements while walking or reaching for objects.
• Hand-flapping and repetitive movements, which may increase with excitement.

Seizures

Seizures affect approximately 80% of people with AS and typically begin between 1 and 3 years of age. Common seizure types include:

• Generalized tonic-clonic seizures (stiffening and jerking movements)
• Absence seizures (brief staring episodes)
• Myoclonic seizures (sudden muscle jerks)
• Atonic seizures (sudden loss of muscle tone, causing falls)

Seizure frequency may decline with age, but they often require lifelong management with antiepileptic medications.

Sleep Problems

Sleep disturbances are common in AS, with affected people experiencing:

• Difficulty falling asleep and frequent night awakenings.
• Circadian rhythm disruption and decreased sleep requirement.

Other Associated Features

• Feeding difficulties in infancy, leading to poor weight gain.
• Tongue thrusting and excessive drooling.
• Strabismus (crossed eyes) and other vision problems.
• Gastrointestinal issues, including constipation and reflux.

Do Symptoms Improve with Age?

While movement, sleep, and hyperactivity issues may improve with age, adults with AS often maintain their happy and excitable personalities and require lifelong support for daily living activities.

Complications

As people with AS grow older, they may develop:

• Scoliosis – Curvature of the spine, which may require bracing or surgery.
• Obesity – Reduced mobility can lead to excessive weight gain.
• Feeding and swallowing issues – May persist into adulthood, requiring modified diets or feeding support.

Angelman Syndrome and Fascination with Water

Many people with Angelman Syndrome exhibit an intense fascination with water, which may include activities such as splashing, playing in puddles, or fixating on moving water sources like fountains and sinks. The underlying reason for this behavior is not fully understood, but it may be linked to sensory-seeking tendencies commonly observed in AS.

Risks of Drowning

While this fascination can be a source of enjoyment, it also poses significant safety risks due to:

• Poor coordination and motor impairments, making swimming difficult.
• Limited danger awareness, increasing the likelihood of accidental drowning.
• Seizures, which may occur unexpectedly in water.

Caregivers should take extra precautions, including:

• Strict supervision around water bodies (pools, bathtubs, lakes).
• Using life jackets when near water.
• Enrolling in adapted swimming lessons to improve water safety skills.

Diagnosis of Angelman Syndrome

Genetic Testing and Diagnostic Process

Diagnosing Angelman syndrome requires both clinical assessment and genetic testing.

DNA Methylation Testing (Detects 80% of cases)

• A DNA methylation test is the first-line genetic test for AS.
• It identifies abnormal UBE3A gene imprinting, which can be caused by maternal deletions, uniparental disomy (UPD), or imprinting defects.

Parental DNA Pattern Testing

• If a methylation defect is detected, further testing determines whether it is caused by UPD or an imprinting defect.

Fluorescent In Situ Hybridization (FISH) and Chromosomal Microarray (CMA)

• Used to detect large deletions on chromosome 15.
• FISH helps identify missing chromosome segments in cases where a large portion of maternal chromosome 15 is absent.

UBE3A Gene Sequencing (Detects 11% of cases)

• For people with normal DNA methylation but AS symptoms, UBE3A sequencing is performed to look for point mutations in the gene.

Electroencephalogram (EEG) for Seizures

• Many children with AS have a unique EEG pattern, even before seizures appear.
• EEG findings in AS often show:
  • High-amplitude slow waves.
  • Generalized spikes or sharp waves.
  • Patterns resembling Lennox-Gastaut Syndrome.

Differential Diagnosis of Angelman Syndrome

AS shares overlapping symptoms with several other neurodevelopmental disorders, which can sometimes delay diagnosis. Key conditions that need to be ruled out include:

• Autism Spectrum Disorder (ASD)
  • Similarities: Impaired communication and repetitive behaviors.
  • Differences: Individuals with AS have strong social interest and frequent smiling, while autistic children may struggle with social engagement.
• Cerebral Palsy (CP)
  • Similarities: Motor delays, movement difficulties, ataxia.
  • Differences: CP typically results from birth injuries, whereas AS is genetic and has a distinct happy demeanor and hand-flapping.
• Prader-Willi Syndrome (PWS)
  • Similarities: Both involve chromosome 15 abnormalities, hypotonia, and developmental delays.
  • Differences: PWS causes severe food-seeking behavior and obesity, while AS is characterized by hyperactivity and laughter.

By using genetic testing, EEG analysis, and clinical observation, doctors can accurately diagnose Angelman Syndrome and differentiate it from similar conditions.

Treatment and Management of Angelman Syndrome

While there is no cure for Angelman Syndrome, early intervention and supportive therapies can significantly improve quality of life. Treatment focuses on managing symptoms, improving communication, enhancing mobility, and addressing associated medical issues.

Early Intervention

Early therapy can help children with AS develop essential motor, communication, and life skills. Recommended interventions include:

• Physical Therapy (PT):
  • Helps improve muscle strength, balance, and coordination.
  • Supports independent movement and walking.
• Occupational Therapy (OT)
  • Aims to improve fine motor skills, daily activities, and self-care.
  • Helps with adaptive equipment use, such as braces or supportive seating.
• Speech Therapy and Alternative Communication
  • Most people with AS have limited or absent speech.
  • Augmentative and Alternative Communication (AAC) tools, such as picture exchange systems and speech-generating devices, can enhance communication.

Seizure Management

Seizures occur in 80% of people with AS and typically require antiepileptic medications. Since seizures may change over time, regular monitoring by a neurologist is essential to adjust medications as needed.

Behavioral Therapies

Managing hyperactivity, short attention span, and impulsivity in AS requires structured behavioral approaches:

• Applied Behavior Analysis (ABA): Reinforces positive behaviors and helps reduce self-injurious or disruptive actions.
• Sensory Integration Therapy: Addresses sensory-seeking behaviors (e.g., fascination with water, hand-flapping).
• Routine and Visual Schedules: Help reduce anxiety and improve predictability in daily activities.

Sleep Training

Sleep disturbances are common in AS, and strategies for better sleep include:

• Consistent bedtime routines.
• Using white noise or weighted blankets for comfort.
• Melatonin supplements (under medical supervision).

Dietary Management

Individuals with AS often experience feeding difficulties and gastrointestinal (GI) issues such as reflux or constipation. Recommended strategies include:

• Soft, easy-to-chew foods for those with chewing/swallowing difficulties.
• High-fiber diets to prevent constipation.
• Specialized feeding therapy for infants with poor sucking reflexes.

Medical Care

Lifelong regular checkups are necessary to manage associated health conditions:

• Orthopedic care for scoliosis or joint stiffness.
• Gastroenterology support for feeding and digestion issues.
• Vision and dental care to monitor for strabismus and teeth grinding.

Through multidisciplinary care, people with AS can achieve better mobility, communication, and overall well-being.

Living with Angelman Syndrome

AS is a lifelong neurogenetic disorder, but people can have a normal lifespan with proper medical care and supportive therapies. On average, people with AS live into their 60s or beyond, though complications such as seizures, mobility issues, and feeding difficulties can impact health outcomes.

AS is not a progressive disorder, meaning symptoms do not worsen over time. However, challenges such as intellectual disability, movement difficulties, and speech impairment persist throughout life. Some symptoms, like seizures and sleep disturbances, may improve with age.

Marea Bourke, a resident of the Stockton Centre in Australia, lived to the age of 78 and is believed to be the longest-living person with Angelman syndrome. This highlights the possibility that people with AS can live well into their senior years, particularly with good medical support and a structured care plan.

Research and the Future of Angelman Syndrome Treatment

Exciting advances in gene therapy and molecular treatments offer hope for targeted interventions in AS.

Antisense Oligonucleotide (ASO) Therapy

• ASO therapy targets the UBE3A gene, attempting to reactivate the silenced paternal copy.
• Recent studies indicate that ASO therapy can restore brain activity, improve sleep patterns, and enhance cognitive function.

Gene Editing Approaches (CRISPR and Epigenetic Modulation)

• Researchers are exploring CRISPR-based therapies to correct UBE3A mutations at a genetic level.
• Epigenetic drugs aim to modify DNA methylation patterns, potentially reactivating the paternal UBE3A gene.

Pharmacological Treatments

• New drug trials are investigating medications that enhance synaptic function and cognitive development in AS.
• Recent discoveries highlight novel compounds that may improve communication and motor function.

Ongoing research into ASO therapy, gene editing, and new pharmacological treatments could transform the management of Angelman Syndrome in the coming years. While these therapies are still in clinical trials, they represent a promising step toward improving the quality of life for people with AS.

FAQs

What is the Difference Between Angelman Syndrome and Prader-Willi Syndrome?

Both Angelman Syndrome and Prader-Willi Syndrome are genetic disorders caused by problems with chromosome 15, but they have distinct features:

• AS typically presents with developmental delays, seizures, movement problems, and a happy, excitable demeanor.
• PWS is marked by insatiable hunger, obesity, short stature, and intellectual disability.

The primary difference lies in the genetic cause:

• AS is caused by loss of function in the UBE3A gene on the mother's chromosome 15.
• PWS results from the loss of paternal gene expression on chromosome 15.

Both conditions share a common origin but lead to different symptoms and challenges.

Are There Prenatal Tests for Angelman Syndrome?

Yes, prenatal testing can detect Angelman Syndrome through non-invasive prenatal screening (NIPS), which analyzes fetal DNA from the mother's blood. Genetic testing can detect the abnormalities associated with AS, such as a UBE3A gene deletion or other mutations, early in pregnancy. However, diagnostic confirmation typically requires genetic testing after birth.

Can Angelman Syndrome Be Prevented?

Angelman Syndrome cannot be prevented as it is caused by genetic mutations that typically occur de novo (not inherited from the parents). However, genetic counseling can be helpful if there is a family history of AS, especially for parents who may be carriers of imprinting defects or other genetic changes. Prenatal testing and early detection can also aid in identifying AS during pregnancy.

Why Does Angelman Syndrome Cause Happiness?

One of the hallmark traits of Angelman Syndrome is an often happy and excitable demeanor, which can include frequent smiling, laughter, and social interaction. This behavior is believed to be related to neurological and genetic factors affecting areas of the brain involved in mood regulation and social behaviors, particularly in regions like the hypothalamus and cortex. Though the exact cause remains unclear, it is thought that the UBE3A gene deficiency impacts brain areas responsible for emotions.

What is Mosaic Angelman Syndrome?

Mosaic Angelman Syndrome occurs when only some cells in the body have the genetic changes responsible for AS, while others do not. This results in a milder form of the disorder, where people may exhibit fewer or less severe symptoms compared to those with the full syndrome. The condition occurs when there is a mosaic pattern of genetic mutations (such as a partial deletion of UBE3A or a mutated gene), which can lead to a variable expression of symptoms.

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