# 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