Angelman Syndrome
Summary
Angelman syndrome (AS) is a rare neurogenetic disorder caused by loss of function of the maternally inherited UBE3A gene on chromosome 15q11-q13. It is characterised by severe intellectual disability, absent or minimal speech, movement disorders (ataxia, tremor), distinctive behaviours (frequent laughter, happy demeanour, hand-flapping), and seizures. The syndrome results from genomic imprinting — the paternal UBE3A allele is normally silenced in neurons, making the maternal copy critical. Diagnosis is confirmed by genetic testing. Management is supportive and multidisciplinary, focusing on seizure control, communication strategies, developmental support, and family education. Affected individuals require lifelong care but can live into adulthood.
Key Facts
- Definition: Neurogenetic disorder from loss of maternal UBE3A gene function on chromosome 15q11-q13
- Prevalence: 1 in 12,000 to 1 in 20,000
- Inheritance: Sporadic in most cases (deletion); recurrence risk varies by mechanism
- Key Mnemonic: "Angelman = MAternal" (contrast with Prader-Willi = Paternal)
- Classic Features: Severe ID, minimal speech, ataxia, seizures, happy demeanour, microcephaly
- Key Management: Antiepileptics for seizures; AAC for communication; multidisciplinary support
- Critical Genetic Difference: Deletion same region (15q11-q13) as Prader-Willi but from opposite parent
Clinical Pearls
"A for Angelman, A for mAternAl": Angelman syndrome results from loss of the MATERNAL copy of the UBE3A gene. Prader-Willi syndrome results from loss of the PATERNAL copy of genes in the same chromosomal region.
"Happy Puppet" No More: The historic term "Happy Puppet Syndrome" is considered offensive and should not be used. Use "Angelman syndrome" only.
Avoid Carbamazepine and Vigabatrin: These antiepileptics can worsen seizures in Angelman syndrome. Valproate and levetiracetam are typically first-line.
Why This Matters Clinically
Angelman syndrome requires early recognition for appropriate developmental support, seizure management, and family counselling. The distinctive behavioural phenotype (happy demeanour, laughter) can sometimes delay concern in early infancy. Genetic diagnosis enables accurate recurrence risk counselling. Seizures are often difficult to control and significantly impact quality of life. With appropriate support, individuals with AS can lead fulfilling lives.
Incidence & Prevalence
- Prevalence: 1 in 12,000 to 1 in 20,000 live births
- No sex predilection: Males and females equally affected
- No ethnic predilection: All ethnicities equally affected
- Trend: Increasing recognition with improved genetic testing
Demographics
| Factor | Details |
|---|---|
| Age of Diagnosis | Typically 3-7 years; may be delayed if features subtle |
| Sex | Equal (X-linked inheritance NOT involved) |
| Ethnicity | No predilection |
| Lifespan | Near-normal life expectancy with appropriate care |
Genetic Mechanisms and Recurrence Risk
| Mechanism | Frequency | Recurrence Risk |
|---|---|---|
| De novo deletion | 70% | <1% |
| UBE3A point mutation | 11% | Up to 50% if mother carries |
| Paternal uniparental disomy (UPD) | 3-7% | <1% |
| Imprinting centre defect | 2-3% | Up to 50% if inherited |
| Unknown (clinical diagnosis only) | 10-15% | Empiric ~10% |
Mechanism
Step 1: Genomic Imprinting at 15q11-q13
- This chromosomal region is subject to genomic imprinting
- Several genes are expressed from only one parental allele
- UBE3A is normally expressed from maternal allele only in neurons (paternal silenced)
Step 2: Loss of Maternal UBE3A Function
- Multiple mechanisms lead to loss of functional maternal UBE3A:
- Deletion of maternal 15q11-q13 (~5-7 Mb, including UBE3A)
- UBE3A mutation (point mutations, small deletions)
- Paternal uniparental disomy (two copies from father, none from mother)
- Imprinting defect (maternal allele silenced like paternal)
Step 3: Neuronal Consequences
- UBE3A encodes E3 ubiquitin ligase
- Important in protein degradation pathways
- Loss of UBE3A in neurons leads to:
- Impaired synaptic plasticity
- Abnormal dendritic spine morphology
- Altered neuronal development and function
Step 4: Clinical Phenotype
- Severe intellectual disability
- Impaired motor function (ataxia, tremor)
- Seizures (cortical hyperexcitability)
- Sleep disturbance (reduced melatonin secretion)
- Characteristic behavioural phenotype
Comparison with Prader-Willi Syndrome
| Feature | Angelman Syndrome | Prader-Willi Syndrome |
|---|---|---|
| Parental origin | Maternal loss | Paternal loss |
| Key genes | UBE3A | SNRPN, snoRNAs |
| Key features | Severe ID, seizures, happy, ataxia | Mild ID, hyperphagia, obesity, hypogonadism |
| Birth presentation | Normal or subtle hypotonia | Severe hypotonia, poor feeding |
| Deletion frequency | 70% | 70% |
Symptoms and Signs by Age
Infancy (0-12 months):
Toddler/Early Childhood (1-4 years):
Later Childhood/Adulthood:
Diagnostic Criteria (Williams/Magenis 2005)
Consistent (100%):
Frequent (>80%):
Associated:
Red Flags
[!CAUTION] Red Flags — Urgent attention required if:
- Status epilepticus — Common; requires emergency management
- Prolonged seizures — Many seizure types; can be difficult to control
- Aspiration/choking — Swallowing difficulties, especially with liquids
- Severe self-injury — May occur during behavioural episodes
- Extreme sleep disturbance — Can severely impact family
Structured Approach
General:
- Overall demeanour (characteristically happy, smiling)
- Height/weight (usually normal; may trend to overweight in adulthood)
- Head circumference (microcephaly common from ~2 years)
Neurological:
- Tone: Hypotonia in infancy; may develop increased tone in limbs with age
- Movement: Ataxic wide-based gait, jerky movements, action tremor
- Reflexes: May be brisk
- Speech: Absent or very limited (<6 words typically)
- Nonverbal communication: Often well-developed (pointing, gestures)
Dysmorphic Features:
- Relative or absolute microcephaly
- Wide mouth with widely spaced teeth
- Prominent mandible (in older children/adults)
- Light pigmentation relative to family (in deletion cases)
- Fair hair, blue eyes (more common in deletion cases)
Special Tests
| Test | Findings | Notes |
|---|---|---|
| EEG | Characteristic high-amplitude slow spike-wave (often frontal); delta activity | Pattern can support diagnosis even without clinical seizures; distinctive pattern |
| Head circumference | <3rd centile from ~2 years | Deceleration rather than primary microcephaly |
| Gait assessment | Wide-based, ataxic, stiff-legged | "Jerky" quality to movements |
First-Line (Diagnostic Genetic Testing)
| Test | Methodology | Detects |
|---|---|---|
| DNA methylation analysis | Methylation-specific PCR/MLPA | Distinguishes maternal from paternal alleles; abnormal in ~80% of AS |
| Chromosomal microarray (CMA) | Array CGH | Detects deletions; first-line for developmental delay workup |
| UBE3A gene sequencing | Sanger/NGS | Detects point mutations (if methylation normal but AS suspected) |
| Parental chromosome analysis | FISH, karyotype | Required to identify de novo vs inherited deletion |
Diagnostic Algorithm
- Clinical suspicion → DNA methylation analysis
- If methylation abnormal → FISH/CMA to detect deletion OR UPD analysis
- If methylation normal but strong clinical suspicion → UBE3A sequencing
- If diagnosis confirmed → genetic counselling for recurrence risk
Other Investigations
| Test | Purpose |
|---|---|
| EEG | Assess for characteristic pattern; monitor seizures |
| MRI Brain | Usually structurally normal; may show mild atrophy or non-specific changes |
| Sleep study | Document sleep architecture if considering melatonin |
| Swallowing assessment | If feeding difficulties or aspiration concerns |
| Scoliosis screening | Spinal X-ray in adolescence |
| Ophthalmology | Strabismus, refractive errors common |
Management Algorithm
Multidisciplinary Team
| Specialty | Role |
|---|---|
| Paediatric Neurologist | Seizure management; EEG interpretation |
| Clinical Geneticist | Diagnosis confirmation; family counselling; recurrence risk |
| Developmental Paediatrician | Developmental assessment; coordination of care |
| Speech and Language Therapy | Augmentative and alternative communication (AAC) |
| Physiotherapy | Motor skills; mobility; scoliosis prevention |
| Occupational Therapy | Activities of daily living; sensory integration |
| Dietitian | Nutrition; manage constipation; prevent obesity |
| Sleep Medicine | Manage sleep disturbance |
Seizure Management
| Drug | Notes |
|---|---|
| Valproate | First-line; broad-spectrum |
| Levetiracetam | Common first-line; may worsen behaviour in some |
| Clonazepam/Clobazam | Useful adjunct; beware tolerance |
| Lamotrigine | May be useful; AVOID high doses (can worsen) |
| AVOID Carbamazepine | Can worsen myoclonic and absence seizures |
| AVOID Vigabatrin | Can worsen seizures in AS |
| Ketogenic diet | Considered for refractory cases |
Status Epilepticus: Follow standard paediatric protocol; AS patients may have prolonged seizures — low threshold for benzodiazepine rescue
Sleep Management
| Intervention | Details |
|---|---|
| Sleep hygiene | Regular bedtime, dark room, consistent routine |
| Melatonin | 2.5-10mg at bedtime; first-line pharmacological |
| Behavioural strategies | Reduce stimulation before bed; white noise |
| Address medical causes | Pain, constipation, GORD |
Communication
| Strategy | Details |
|---|---|
| Augmentative and Alternative Communication (AAC) | Picture exchange (PECS), communication boards, speech-generating devices |
| Sign language | Simple signs (Makaton, BSL) often used |
| Encourage non-verbal communication | Gestures, eye gaze |
| Early intervention | Speech and language therapy from infancy |
Behavioural and Safety
- Safety at home: Water safety (fascination with water); locks on doors (wandering); remove hazards
- Behavioural support: Positive behavioural support strategies; manage hyperactivity, mouthing
- Education: Special educational needs provision; 1:1 support typically required
Ongoing Surveillance
| Issue | Monitoring |
|---|---|
| Seizures | Regular neurology review; EEG as needed |
| Scoliosis | Clinical assessment; spinal X-ray in adolescence |
| Weight | Monitor for obesity (especially adulthood) |
| Constipation | Common; stool softeners often needed |
| Vision/hearing | Annual screening |
| Transition to adult services | Plan from age 14+ |
Medical Complications
| Complication | Frequency | Presentation | Management |
|---|---|---|---|
| Seizures | 80%+ | Multiple types (myoclonic, atypical absence, GTC) | Antiepileptics; avoid carbamazepine |
| Status epilepticus | Common | Prolonged seizures | Emergency protocol; rescue medication |
| Scoliosis | 40-70% (adulthood) | Spinal curvature | Monitoring; bracing; surgery if severe |
| Constipation | Very common | Infrequent bowel movements, discomfort | Dietary fibre, laxatives |
| GORD | Common | Regurgitation, discomfort | PPIs, positioning |
| Aspiration | Variable | Coughing with feeds, recurrent chest infections | Swallowing assessment; thickened feeds |
| Obesity | Common in adults | Weight gain | Dietary management; exercise |
| Strabismus | 30-40% | Eye misalignment | Ophthalmology referral |
Developmental/Behavioural
| Issue | Impact |
|---|---|
| Severe intellectual disability | IQ typically 20-40; requires lifelong support |
| Absent/minimal speech | Communication barrier; AAC essential |
| Sleep disturbance | Affects child and family |
| Hyperexcitability/short attention | Impacts learning and daily life |
Natural History
Angelman syndrome is a lifelong condition. With appropriate supportive care, individuals can live into adulthood (near-normal life expectancy). Motor function and seizure control may improve somewhat with age, though intellectual disability and communication difficulties persist. Transition to adult services is a critical period.
Outcomes Summary
| Domain | Outcome |
|---|---|
| Life expectancy | Near-normal with good care |
| Ambulation | 75-90% walk independently (often with ataxic gait) |
| Speech | Most have <6 words; rely on AAC |
| Independent living | Not anticipated; requires lifelong support |
| Seizures | May improve in adulthood; some become seizure-free |
| Quality of life | Can have good quality of life with support and engagement |
Prognostic Factors
Better Outcomes:
- Earlier diagnosis and intervention
- Good seizure control
- Effective communication strategies
- Family and community support
- Access to specialised services
Poorer Outcomes:
- Refractory seizures
- Severe feeding difficulties
- Recurrent aspiration
- Development of severe scoliosis
- Lack of support services
Key Guidelines
- Williams et al. (2010) Angelman Syndrome: Management Guidelines — Comprehensive consensus guidelines covering diagnosis, seizure management, communication, and surveillance. PMID: 19876054
- Foundation for Angelman Syndrome Therapeutics (FAST) — Patient advocacy with research and clinical guidelines.
- American Society of Human Genetics (ASHG) — Genetic testing recommendations.
Key Research
Gene Therapy/ASO Research — Active clinical trials investigating antisense oligonucleotides (ASOs) to reactivate silenced paternal UBE3A copy (e.g., GTX-102).
- Early-phase trials ongoing
- Potential to address root cause
- [ClinicalTrials.gov identifiers: multiple]
Minocycline Studies — Investigated for potential neuroprotection; results mixed; not currently recommended routine.
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Valproate for seizures | Expert consensus | Commonly used; empirical evidence |
| Melatonin for sleep | 2b | Controlled studies show benefit |
| AAC for communication | 2a | Standard of care; observational evidence |
| Avoid carbamazepine | Expert consensus | Reports of seizure worsening |
| Scoliosis surveillance | Expert consensus | High prevalence justifies screening |
What is Angelman Syndrome?
Angelman syndrome is a rare genetic condition that affects the nervous system and causes developmental problems. Children with Angelman syndrome have intellectual disability, difficulty speaking, problems with balance and walking, and often have seizures. A distinctive feature is their typically happy, excitable personality with frequent smiling and laughter.
Why does it happen?
Everyone has two copies of each gene — one from each parent. For most genes, both copies work. But for some genes, only one copy is meant to be active depending on which parent it came from. In Angelman syndrome, the copy from the mother of a specific gene called UBE3A is lost or doesn't work, and the father's copy is naturally switched off. Without a working copy, the brain doesn't develop properly.
This is different from Prader-Willi syndrome, where the same area of the chromosome is affected, but it's the father's copy that's missing.
How is it treated?
There is no cure yet, but much can be done to help:
- Seizures: Medications to control seizures (some drugs to avoid — ask your neurologist)
- Communication: Sign language, picture boards, or electronic devices to help communicate
- Physical therapy: Help with walking and balance
- Sleep: Melatonin and sleep routines to help with severe sleep problems
- Support: Special educational support, respite care for families
What to expect
- Children with Angelman syndrome will need lifelong care and support
- With good care, they can live into adulthood
- Many learn to walk independently, though with an unusual gait
- Speaking is very limited, but many communicate well using signs or devices
- Seizures often improve with age
- Despite challenges, people with Angelman syndrome often have a happy disposition and can enjoy life with their families
When to seek help
- If your child has a prolonged seizure (more than 5 minutes) — call 999
- If you notice new difficulties with swallowing or recurrent chest infections
- If sleep disturbance is severely affecting the family — discuss with your doctor
- For genetic counselling if you are planning another pregnancy
Primary Guidelines
- Williams CA, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140(5):413-418. PMID: 16470747
- Pelc K, et al. Epilepsy in Angelman syndrome. Seizure. 2008;17(3):211-217. PMID: 17977023
Key Research
- Meng L, et al. Towards Treatment of Angelman Syndrome. Trends Mol Med. 2015;21(4):217-226. PMID: 25771097
- Thibert RL, et al. Epilepsy in Angelman syndrome: A questionnaire-based assessment of the natural history and current treatment options. Epilepsia. 2009;50(11):2369-2376. PMID: 19453717
- Bird LM. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet. 2014;7:93-104. PMID: 24876791
Further Resources
- Angelman Syndrome Foundation (US): www.angelman.org
- ASSERT (UK Angelman support): www.angelmanuk.org
- Foundation for Angelman Syndrome Therapeutics (FAST): www.cureangelman.org
- Unique (Rare Chromosome Disorder Support Group): www.rarechromo.org
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists. This content does not constitute medical advice for individual patients.