Handbook of Genetic Counseling/Angelman Syndrome-1
Angelman Syndrome MIM#105830
Etiology
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- 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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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%
- 3-5 MB deletion
- 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
- Includes:
- 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
- High risk
Management
edit- 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
edit- Family reaction: guilt, sadness, anger, fear, denial, shock, relief
- Financial pressures
- Lifelong management
- Concerns about future pregnancies