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Genetic counseling: Angelman Syndrome-1

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Angelman Syndrome MIM#105830

EtiologyEdit

File:Ube3a.jpg
  • 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 devided 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
  • There are recent data showing that artificial reproductive technology (mainly intraspermal sperm injection) interferes with establishment of imprint and presispose to imprinting disorders (eg.: AS/PWS, Beckwith-Wiedemanm syndrome(BWS))

Clinical featuresEdit

  • 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 + inapropriate 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 testingEdit

  • 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 (normaly 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

DiagnosisEdit

  • 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 diagnosisEdit

  • 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 membersEdit

  • 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

ManagementEdit

  • 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 issuesEdit

  • Family reaction: guilt, sadness, anger, fear, denial, shock, relief
  • Financial pressures
  • Lifelong management
  • Concerns about future pregnancies

Support informationEdit

ResourcesEdit

  • GeneClinics. "Angelman Syndrome" Web: [1]
  • ORPHANET [2]
  • European Directory of DNA Diagnostic Laboratories [3]
  • NCBI Genes and Disease Webpage [4]
  • GeneImprint [5]



Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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