Handbook of Genetic Counseling/Angelman Syndrome-1

Angelman Syndrome MIM#105830

Etiology

Genetic map of 15q11-q13 region

• 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

• Angelman Syndrome Foundation,
• Angelman Syndrome Support Education and Research Trust

Resources

• GeneClinics. "Angelman Syndrome" Web:
• ORPHANET
• European Directory of DNA Diagnostic Laboratories
• NCBI Genes and Disease Webpage
• GeneImprint