# Handbook of Genetic Counseling/Angelman Syndrome-2

Angelman Syndrome

## Introduction

* Introduce myself
* What are the major concerns that you would like to have addressed today?
* Who referred you to genetics?
* Outline session
** obtain medical history and family history
** Dr. Saal will come in and do physical exam
** discuss condition and testing options
** address specific concerns

## Medical History

* complete intake
** seizures?
** medications?
** sleeping patterns?
** communications skills?
** hyperactivity?
** developmental assessment?
** services received?
** unusual behaviors? laughter? generally happy?
** problems with balance? walking?
** MRI?
* complete pedigree

## Incidence

* 1/12,000-1/20,000

## Clinical Features

* Feature present in about 100% of patients
** normal prenatal and birth history
*** normal birth weight and head circumference
*** no major birth defects
** normal metabolic and hematologic profile
** structurally normal brain on MRI
*** mild cortical atrophy or dysmyelination possible
** delayed motor development
*** apparent by 6-12months
*** usually severe
** speech impairment
*** usually < 1 or 2 words
*** receptive language better than expressive language
** movement and balance disorder
*** abnormal gait
*** tremulous movements of limbs
** Unusual behaviors
*** Frequent laughter and smiling/happy demeanor
*** Excitability
*** Hyperactivity
*** Short attention span
* Features Present in more than 80% of patients
* Microcephaly
** caused by delayed head growth
** present by age 2
* Seizures
** Beginning by age 3
* Abnormal EEG
** Characteristic large amplitude slow-spike waves
* Features found in 20-80% of patients
** Strabismus
** Hypopigmentation of skin and eyes
** Feeding problems in infancy
** Wide mouth, wide spaced teeth
** Increased sensitivity to heat
** Sleep disturbances

## Management

* Behavioral modification for undesirable/socially unacceptable behaviors
* Medication for seizures
* Generally do not receive medication for hyperactivity
* Occupation therapy for fine motor control
* Speech therapy focusing on nonverbal means of communication
* Safe, confining bedroom for nighttime sleeplessness
* Monitoring for onset of scoliosis

## Genetics

* Caused by loss of maternal contribution of region 15q11-q13
** 65-75% of patients have 3-5Mb interstitial deletion
** 3-7% of patients have paternal uniparental disomy
** 2-6% of patients have imprinting defect
** 5-11% of patients have mutations in the UBE3A gene within this region
** 11-20% of patients have another unknown cause

## Molecular Testing

* DNA methylation analysis
** 78% of patients with a deletion, uniparental disomy, or an imprinting defect are detected this way
** further testing is required to distinguish between these types
*** FISH analysis can detect deletions (70% of patients)
*** DNA polymorphism testing can detect uniparental disomy
*** Patients with imprinting defects have 15q11-q13 polymorphisms from both parents
**** imprinting center defect characterization available on research basis only
* UBE3A mutation analysis
** 11% of patients with Angelman syndrome have identifiable mutations

## Recurrence Risks

* Families Genetic Mechanism Risk to Siblings
** 65-75% 3-5Mb deletion <1%
** <1% unbalanced translocation as high as 50%
* small interstitial deletion
** 3-7% paternal uniparental disomy <1%
** <1% uniparental disomy with approaching 100% Robertsonian translocation
** 1-3% imprinting defect as high as 50% (if deletion in imprinting center mother has deletion)
** 1-3% imprinting defect likely <1% without deletion
** 11% UBE3A mutation as high as 50% if mother has deletion
** 10-15% other unidentifiable cause most cases not familial (but could be as high as 50%)

## Psychosocial Issues

* Who is involved in care of patient?
* What is the living situation?
* How will having a diagnosis change care and management?
* How will having a diagnosis affect you?
* Are there concerns about recurrence risks?

## References

* Geneclinics: Angelman syndrome
* Smith's Recognizable Patterns of Human Malformations
* Clinical Genetics Lecture

## Notes

The information in this outline was last updated in 2002.