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.