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.