Handbook of Genetic Counseling/Angelman Syndrome-1

Angelman Syndrome MIM#105830

Etiology

Neurobehavioural disorder caused by deficient expression or function of E6AP ubiquitin protein ligase 3A (UBE3A gene product)
Due to loss of maternal imprinting in 15q11-q13 region (AS/PWS region) by one of several mechanisms (patients are divided into classes I-V based on these mechanisms):
- I. Interstitial deletion of the region on copy of chromosome 15 inherited maternally (~4 Mb) (65-75%)
- II. Paternal uniparental disomy (UPD) - father contributes both copies (3-7%)
- III. Imprinting defects (2-6%)
- IV. Mutation in the UBE3A gene (5-11%)
- V. Unknown mechanisms (11-20%)
Patients with deletions usually more severely affected
Affects 1 in 12,000 - 40,000 in population
The sister syndrome, known as Prader-Willi syndrome, is caused by the loss of the paternally-imprinted copy of the same region. The symptoms are quite different.
There are recent data showing that artificial reproductive technology (mainly intraspermal sperm injection) interferes with establishment of imprint and presispose to imprinting disorders (e.g.: AS/PWS, Beckwith-Wiedemanm syndrome(BWS))

Clinical features

Key findings (~100%)
- Severe developmental delay by 6-12 months without loss of skills
- Speech impairment (no or minimal use of words)
- Movement or balance disorder (gait ataxia, tremulous movement of limbs, hypermotoric behaviour)
- Happy demeanor ("happy puppet"), excitability + hand flapping + inappropriate laughter, short attention span
Common findings (80%)
- Delayed or disproportionately slow growth in head circumference
- Seizures (usually before age 3)
- Abnormal EEG (large amplitude slow spike and triphasic waves)
Associated findings (20-80%)
- Flat back of head
- Strabismus
- Hypopigmentation of skin and eyes
- Tongue thrusting, sucking/swallowing disorders, excessive chewing and mouthing behaviors
- Feeding problems during infancy
- Wide mouth, wide-spaced teeth, prominent mandible (prognathia)
- Hyperactive tendon reflexes
- Sleep disorders
- Uplifted flexed arms while walking
- Increased sensitivity to heat
- Sleep disturbance
- Fascination with water

Diagnostic testing

DNA methylation analysis
- Most sensitive test (identifies 80% of cases)
- Detects deletions, uniparental disomy, and imprinting defects - such patients will have only unmethylated SNRPN (small nuclear ribonuclear protein-associated polypeptide N) alleles (normally would be one maternal methylated and one paternal unmethylated)
FISH
- Performed if DNA methylation analysis is positive to look for deletion in 15q11-q13
- May do FISH testing first for children over 5 years of age with classical symptoms and hypopigmentation
DNA polymorphism analysis
- Can distinguish between uniparental disomy and imprinting defects
- Used if FISH analysis is normal but DNA methylation is positive
UBE3A sequence analysis
- Performed if DNA methylation analysis is normal
- Identifies UBE3A mutations not detected by other methods
High resolution chromosome analysis
- Can detect rare chromosomal rearrangement that will alter recurrence risk
- Should be performed for all patients
EEG (electroencephalography)
- 2-3 Hz large-amplitude slow waves
- normal EEG does not exclude diagnosis

Diagnosis

Combination of clinical features, molecular genetic testing, and cytogenetic analysis
Unique clinical features not apparent until about 1 year old
- Developmental delay first noted at 6 months
- Can take several years until diagnosis is apparent

Differential diagnosis

Prader-Willi syndrome
- Also has deletion in 15q11-q13
- Distinguished by parent-specific methylation studies
Inborn error of metabolism or oxidative phosphorylation ruled out by testing
Rett syndrome (in females)
- Rett syndrome patients do not have characteristic happy personality
- Angelman syndrome does not cause neurological regression
Mowat-Wilson syndrome
- typical dysmorphic face pattern
22q13 deletion
X-linked alpha-thalassaemia/mental retardation syndrome (ATR-X) (in males)
- small triangular nose + tenting of the upper lip

Risk for family members

Risks to siblings depends on genetic cause of syndrome
- 3-5 MB deletion
  - Sibling risk <1%
  - Mothers should have chromosomal analysis to look for balanced translocation
- Unbalanced chromosomal translocation or inherited small interstitial deletion
  - Sibling risk as high as 50%
  - Depends on whether rearrangement is inherited or de novo
- Paternal uniparental disomy
  - Sibling risk <1% if no translocation
  - Risk 100% if father has 15;15 Robertsonian translocation
  - Fathers should have chromosomal analysis
- Imprinting defect
  - Sibling risk 50% for defect in imprinting center if mother also has defect in imprinting center
  - Risk about <1% if imprinting defect does not involve deletion of imprinting center
- UBE3A mutation
  - Sibling risk as high as 50% if mother also has a mutation
  - Can also be de novo mutation
- "Other" mutations
  - Most cases are not familial
  - Risk may be as high as 50%
Prenatal testing
- High risk
  - Includes:
    - Parents with one child with AS caused by deletion or uniparental disomy for reassurance
    - Parents with one child with AS caused by a UBE3A mutation even if mother has tested negative for the mutation as she may be mosaic
    - Testing for an inherited translocation involving chromosome 15 by FISH, DNA methylation, or polymorphism analysis (parent-of-origin studies)
  - Should only be done once genetic cause of syndrome has been established
  - Amniocentesis or CVS
  - Genetic alterations in 15q11-q13 detected by FISH/chromosomal analysis and/or DNA testing
- Low risk
  - No family history of Angelman syndrome
  - Should be considered in several cases
    - If cytogenetic studies from CVS or amniocentesis indicate 15q11-q13 deletion, FISH or parent-of-origin studies can be done
    - If trisomy 15 or mosaic trisomy 15 is detected on CVS but amniocentesis reveals 46 chromosomes, parent-of-origin studies can be done
    - If de novo translocation of chromosome 15 or dicentric chromosome 15 marker is detected, FISH and parent-of-origin studies can be considered

Management

Multidisciplinary child development team care
Seizures treated with anticonvulsant medications
Developmental delay requires educational training and therapy
- Physical therapy
- Occupational therapy
Speech therapy focusing on non-verbal methods of communication
- Picture cards or communication boards
- Sign language
- Individualized education program
Hyperactivity
- Behavioral modification effective to prevent disruptive or dangerous behaviors
- Some may benefit from use of stimulant medications (Ritalin)
Sleep disorders may require sedative or administration of melatonin before bed
Feeding problems may require special strategies to deal with weak sucking or gastroesophageal reflux
Strabismus needs surgical repair
Orthotic bracing or surgery for orthopedic problems
Scoliosis may require bracing or surgical rod stabilization
Dietary monitoring if excessive appetite

Psychosocial/genetic counseling issues

Family reaction: guilt, sadness, anger, fear, denial, shock, relief
Financial pressures
Lifelong management
Concerns about future pregnancies

Support information

Resources

GeneClinics. "Angelman Syndrome" Web: [1]
ORPHANET [2]
European Directory of DNA Diagnostic Laboratories [3]
NCBI Genes and Disease Webpage [4]
GeneImprint [5]