Angelman Syndrome

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Angelman Syndrome

• Trevor Dang, Parnika Gupta, Patrick Ho-Ly and
  Surayya Kassam
• November 16, 2012
• Dr. Hampsen, PHM142

PHM142 Fall 2012 Coordinator Dr. Jeffrey
Henderson Instructor Dr. David Hampson
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What is Angelman Syndrome?

• A complex neuro-genetic disorder
• Caused by the loss of the normal maternal
  contribution to a region of chromosome 15
• Impairment is dependent on their relative
  frequency in affected individuals
• Consistent (100), Frequent (gt80), Associated
  (20-80)
• Affects an estimated 1 in 12,000 to 20,000 people

3
What is Angelman Syndrome?

• Behavioural Aspects
• Happy excitable demeanor
• Hand-flapping movements
• Hyperactivity
• Trouble sleeping

• Progression
• Less excitable
• Improves sleep
• Intellectual, speech impairment remain
• Normal life expectancy

4
Diagnosis

• First suspected on the basis of the behavioral
  phenotype
• Features do not manifest until 1 year
• EEG with a pattern of large-amplitude
  slow-spike waves

5
Clinical Diagnosis

• Chromosome size, shape and number
• Missing chromosomes (FISH)
• Parental DNA Pattern
• DNA methylation
• Gene Mutation

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Biochemistry Link

• Complex genetic basis
• First single-gene disorder of ubiquitination
  pathway (UBE3A)
• 4 known genetic abnormalities involving the
  chromosome 15q11-13 region

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UBE3A

• Maternally inherited
• Main features of AS result
• from deficient expression or
• function of this allele
• Mechanisms that disrupt UB3EA
• Deletions
• UPD
• Imprinting defects
• Mutations

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Imprinting mutations

• Defect in resetting imprint mechanism during
  gametogenesis
• Small deletions, abnormal DNA methylation
• E6-AP ubiquitin-protein ligase (UBE3A) gene
  involved
• Deficient expression/function leads to many
  different issues

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Mutations

• UBE3A mutations cause protein truncation
• Missense, frame shift
• Complete or partial deletion
• Intragenic deletion

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Uniparental Paternal Disomy

• The inheritance of two paternal chromosome
  15s with
• no maternal chromosome 15 contribution
• More specifically, absence/deletion within
  maternal
• 15q11-13
• Maternal Angelmans locus is essential for
  normal fetal
• development

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How Uniparental Paternal Disomy Arises
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How Uniparental Paternal Disomy Arises (contd)

• Two main mechanism in Meiosis and Mitotic Errors
• A) Fertilization between a disomic and a
  nullisomic gamete.
• B) Trisomic Conceptus formation followed by
  single chromosome deletion
• 2 spontaneous abortion rate due to trisomic 15

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Maternal Deletion

• Microscopic cytogenetic analysis with silver
  staining and GTG-banding
• Shorter arms of chromosome 15 with 15q11-13
  maternal deletion
• Deleted maternal chromosome identified apart from
  paternal chromosome via Silver Staining
• ? Paternal Ag staining at tip of the of the
  cells
• ? Maternal Ag staining across centre of
  satellites

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Treatment

• No cure
• Alleviate neurological/developmental symptoms
• Level of development varies
• Early diagnosis
• essential

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Treatment contd

• Anti-seizure medication
• Physical/occupational therapy
• Communication therapy
• Behavior therapy

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Prognosis/Conclusion

• Children do not regress
• UBE3A expressed in the hippocampus and
  cerebellum precise role in pathogenesis of AS is
  still unknown
• Current research identify proteins involved in
  symptomology - can be useful for developing
  treatments
• National Institute of Neurological Disorders and
  Stroke

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References

• Clayton-Smith, J., and L. A. E. M. Laan.
  "Angelman syndrome a review of the clinical and
  genetic aspects." Journal of Medical Genetics
  40.2 (2003) 87-95.
• Jill Clayton-Smith. (2010). Angelman syndrome.
  Journal of Pediatric Neurology, 8(1), 97-99.
  Retrieved from http//search.proquest.com/docview/
  217686922?accountid14771
• Jiang, Yong-hui, et al. "Genetics of Angelman
  syndrome." American journal of human genetics
  65.1 (1999) 1.
• Laan, Laura AEM, and Oebele F. Brouwer. "Angelman
  syndrome a review of clinical and genetic
  aspects." Clinical neurology and neurosurgery
  101.3 (1999) 161-170.
• Lalande, M., and M. A. Calciano. "Molecular
  epigenetics of Angelman syndrome." Cellular and
  molecular life sciences 64.7 (2007) 947-960.
• Malcolm, S., et al. "Uniparental paternal disomy
  in Angelman's syndrome." The Lancet 337.8743
  (1991) 694-697.
• Smith, J. Clayton, et al. "Maternal origin of
  deletion 15q1113 in 25/25 cases of Angelman
  syndrome." Human genetics 88.4 (1992) 376-378.
• Williams, Charles A., Daniel J. Driscoll, and
  Aditi I. Dagli. "Clinical and genetic aspects of
  Angelman syndrome." Genetics in Medicine 12.7
  (2010) 385-395.
• "NINDS Angelman Syndrome Information Page."
  National Institute of Neurological Disorders and
  Stroke. National Institute of Health, 7 Oct.
  2011. Web. 8 Nov. 2012. lthttp//www.ninds.nih.gov
  / disorders/angelman/angelman.htmgt.
• "Treatments and Drugs." Mayo Clinic. N.p., 17
  Jan. 2012. Web. 14 Nov. 2012. http//www.mayoclini
  c.com/health/angelman-syndrome/DS01048/DSECTIONtr
  eatments2Dand2Ddrugs.
• "Angelman Syndrome." Medicine Net. Ed. Melissa
  Conrad Stoppler. N.p., 16 Oct. 2007. Web. 14 Nov.
  2012. lthttp//www.medicinenet.com/angelman_syndrom
  e/page3.htmgt.
• "Angelman syndrome Tests and diagnosis -
  MayoClinic.com." Mayo Clinic. N.p., n.d. Web. 15
  Nov. 2012. lthttp//www.mayoclinic.com/health/angel
  man-syndrome/DS01048/DSECTIONtests-and-diagnosisgt
  

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Summary Slide

• A complex neuro-genetic disorder caused by the
  loss of the normal maternal contribution to a
  region of chromosome 15
• First single-gene disorder of ubiquitination
  pathway (UBE3A)
• Mechanisms that disrupt UB3EA
• Deletions
• UPD
• Imprinting defects
• Mutations
• Uniparental Paternal Disomy
• The inheritance of two paternal chromosome 15s
• Absence of maternal 15q11-13
• Treatment anti-seizure medication,
  physical/occupational therapy, communication
  therapy, behavior therapy
• There is no cure
• Normal life expectancy

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Mark Distribution

• Trevor Dang 4/4
• Parnika Gupta 4/4
• Patrick Ho-Ly 4/4
• Surayya Kassam 4/4