Course:MEDG550/Student Activities/Angelman Syndrome

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Angelman Syndrome (AS) is a genetic disorder characterized by developmental delay, seizures, jerky-movements and a happy demeanor. The prevalence of Angelman Syndrome is approximately 1/12 000 – 1/20 000. Both boys and girls are equally affected. [1]

A boy with Angelman Syndrome

Clinical Features[1][2][3][4]

Angelman Syndrome is a neurodevelopmental disorder. The most common features include developmental delay, speech impairment, seizures, sleep problems and jerky movements.

Newborns & Infants

  • feeding difficulties
  • gastroesophageal reflux or vomiting
  • "floppy baby" syndrome
  • microcephaly (small head)
  • developmental delay: lack of cooing or babbling; unable to support own head or pull to stand; delays in walking
  • seizures
  • sleep problems

Children

Children with Angelman Syndrome also have a uniquely happy personality, with frequent laughter and excitability. They also often show hand-flapping movements. Children typically also have hyperactivity (excessive activity), hypermotility (excessive movement) and problems sleeping.

Adults

Although individuals with AS usually do not develop speech, many older children and adults can communicate through pointing or using a communication board. Many individuals with AS continue to have issues with poor sleep and constipation into adulthood. Adults with AS require help with day-to-day activities, and they often live with family or in assisted living facilities. To our knowledge, individuals with Angelman syndrome have a normal life expectancy and can live into older age.

Physical Features

  • flat head
  • abnormal eye alignment (strabismus)
  • protruding tongue
  • wide-spaced teeth
  • flexed arms
  • scoliosis
  • obesity

Inheritance

Everyone typically has 46 chromosomes, the structures that contain our genetic information, we get half of our chromosomes from our mom and half from our dad. Chromosomes come in pairs, so we each typically have two copies of each chromosome, or 23 pairs of chromosomes.

15q11.2-q13 (red) is the region on chromosome 15 which contains UBE3A.

Angelman Syndrome occurs when individuals don't inherit a working copy of the gene from their mother. The UBE3A gene is one of a number of genes located on chromosome 15. It is located within the 15q11.2-q13 region of the chromosome. UBE3A provides the instructions for making a protein called ubiquitin protein ligase E3A. Ubiquitin protein ligase E3A is responsible for breaking down unnecessary proteins in the brain and helping to keep brain cells working normally. [2]

Human male karyotpe high resolution - Chromosome 15.png
Human male karyotype. UBE3A is located on chromosome 15 (red box).

Angelman Syndrome is unique because it depends on which parent passes on the genetic change. Individuals usually inherit two copies of each gene, one from their mother and one from their father. In most cases, both genes are turned on, or working, in the cells of our body. However, in certain areas of the brain, only the UBE3A gene inherited from the mother is turned on. The UBE3A gene inherited from the father is turned off in the same areas of the brain that the UBE3A maternal copy is turned on. This concept of parent-specific gene activation is called genomic imprinting. This means there are special instructions for some genes to be off or on depending on if they are from your mother or father. In Angelman Syndrome, the maternal copy of UBE3A is either missing or not working, meaning that certain areas of the brain have no working UBE3A. When there is no working UBE3A, it results in Angelman Syndrome. This can happen in a few different ways. [5]

  1. Maternal Deletion: A part of chromosome 15 inherited from the mother is missing, including the UBE3A gene. The individual still has one copy of UBE3A inherited from their father, but this copy is turned off.
  2. Paternal Uniparental Disomy: This occurs when a mistake is made and the individual inherits two copies of the chromosome 15 from their father. Both copies of the UBE3A gene are turned off.
  3. Imprinting Defect: An individual inherits one copy of UBE3A from their mother and one copy of UBE3A from their father as usual. However, the copy from their mother is accidentally turned off, in addition to the copy from the father also being inactive. There is an error in the instructions telling the maternal gene to be on in this case.
  4. Disease-causing UBE3A variant: An individual inherits one copy of UBE3A from their mother and one copy of UBE3A from their father as usual. The maternal copy has a spelling change, or mutation, resulting in the gene not working properly. Therefore, the individual has two non-working copies of the gene.
  5. Other: A small number of patients have no genetic mechanism identified.

Management

Individuals with Angelman Syndrome will have a personalized care plan based on the symptoms they are experiencing. This will likely include occupational therapy, which assists with achieving independence in daily tasks or participation in activities, such as play. Physical therapy is sometimes required to work on walking and movement problems a child may have. Speech therapy may be needed to help the child develop non-verbal communication skills. Behavioral therapy is sometimes needed to work on hyperactivity and/or a short attention span. An individualized education plan will be developed for the child to attend school with assistance. [1] [5]

Clinical symptoms such as seizures and sleeping difficulties can be treated with antiepileptics and sedatives. Children will be followed for other secondary symptoms such as feeding difficulties or scoliosis. It is recommended children with Angelman Syndrome have a yearly scoliosis exam as well as assessment for obesity. Some individuals may need surgery to correct the abnormal alignment of their eyes. For those with frequent constipation, laxatives are used regularly. [1] [5]

Individuals with Angelman Syndrome tend to have an average life expectancy. As an individual with Angelman Syndrome gets older, the behavioral features including hyperactivity and hypermotility lessen. [1] [5]

Genetic Testing[1][6]

Molecular testing from a blood test can be helpful in establishing a diagnosis of Angelman syndrome. This type of testing looks at the level of the chromosomes or DNA for changes that explain an individual's features and symptoms. A karyotype or chromosomal microarray which analyzes chromosome 15 on a broad scale may be used to test if someone has Angelman syndrome when they show some features suggestive of the condition.

DNA Methylation Analysis

DNA methylation analysis looks at the imprinting pattern in the 15q11.2-q13 region. This type of testing identifies about 80% of individuals with Angelman syndrome. It detects individuals with AS where the cause is:

  • deletion of the maternal copy of UBE3A
  • uniparental disomy of the paternal copy of chromosome 15
  • an imprinting defect of the maternal copy of UBE3A

UBE3A sequence analysis

Sequencing of the UBE3A gene may be considered if a diagnosis of Angelman syndrome is suspected, but DNA methylation analysis is normal. A normal DNA methylation analysis result suggests that there may be a disease-causing variant or change in UBE3A that prevents the gene from working properly. Sequence analysis looks at each letter in the sequence of the DNA and it has higher resolution than a karyotype or chromosomal microarray test.

Genetic Counselling

Genetic counselling should be offered to families if a diagnosis of Angelman Syndrome is suspected. The chance of reoccurrence in future offspring and risk to other family members depends on the genetic mechanism. Testing during future pregnancies can be done if the genetic mechanism is known. [1] [5]

  1. Deletion of UBE3A:
    • If the mother has a deletion on chromosome 15 including UBE3A:
      • Each child has a 50% risk of having Angelman Syndrome
    • If the deletion is new in the child:
      • There is a very small chance (<1%) of any future children also having Angelman Syndrome
  2. Paternal UPD:
    • If the mother has normal chromosomes:
      • The risk of future children having Angelman Syndrome is less than 1%
    • If the mother has a chromosomal rearrangement:
      • In rare cases, there may have been two copies of the father’s chromosome 15 due to a chromosome problem in the mother. Depending on the chromosome problem, there may be an increased risk of Angelman Syndrome occurring again
  3. Imprinting Defect: This can be due to genetic changes that cause the gene to be accidentally turned off.
    • If the mother carries a genetic change that came from her dad:
      • The risk of future offspring having Angelman Syndrome is 50%
    • If the genetic change causing the gene to be inactive is new in the child:
      • The risk of future offspring having Angelman Syndrome is less than 1%
  4. UBE3A mutation:
    • If the mother has a non-working copy of the UBE3A gene:
      • The risk to future offspring is 50%
    • If the mutation is new in the child:
      • The risk to future offspring is less than 1%

If the father carries a genetic change or deletion in the UBE3A gene, his offspring will not be at risk of Angelman Syndrome. However, if he passes the genetic change to his daughters, their children will have a 50% chance of having Angelman Syndrome. If he passes the change to his son’s, their children will have a 50% chance of Prader-Willi syndrome – a paternally imprinted condition.

Patient Resources

Canadian Angelman Syndrome Society: http://www.angelmancanada.org/

Angelman Syndrome Foundation: http://www.angelman.org/

Angelman UK Society: http://angelmanuk.org/

Intellectual and Developmental Disability Support in the US: http://www.thearc.org/

Foundation for Angelman Syndrome Therapeutics: http://cureangelman.net/understanding-angelman/resources/


References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Dagli AI, Mueller J, Williams CA. Angelman Syndrome. 1998 Sep 15 [Updated 2015 May 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1144/
  2. 2.0 2.1 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.
  3. Gentile, J.K., Tan, W.H., Horowitz, L.T., Bacino, C.A., Skinner, S.A., Barbieri-Welge, R., Bauer-Carlin, A., Beaudet, A.L., Bichell, T.J., Lee, H.S. and Sahoo, T. (2010). A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. Journal of developmental and behavioral pediatrics: JDBP, 31(7), 592.
  4. Larson, A. M., Shinnick, J. E., Shaaya, E. A., Thiele, E. A., & Thibert, R. L. (2015). Angelman syndrome in adulthood. American Journal of Medical Genetics Part A, 167(2), 331-344.
  5. 5.0 5.1 5.2 5.3 5.4 Genetic Home Reference. “Angelman Syndrome”. May 2015. Accessed from: https://ghr.nlm.nih.gov/condition/angelman-syndrome
  6. Ramsden, S. C., Clayton-Smith, J., Birch, R., & Buiting, K. (2010). Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC medical genetics, 11(1), 70.