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

 * 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