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?