Angelman Syndrome

Original Editor - Hannah Angermann, Michelle Griffin, Emily Locker

Top Contributors - Hannah Angermann and Meaghan Rieke  

Description of Angelman Syndrome

Angelman Syndrome is a complex genetic disorder affecting the nervous system. It is characterized by severe learning difficulties, motor dysfunction, seizure disorder, and often a happy, sociable disposition.

Prevalence

The estimated incidence of Angelman Syndrome is 1 in every 12000-20000 live births; with males and females being affected equally [1]. Cases have been reported all over the world, with no preference for specific races or populations [2]

Pathological Process

  • Angelman Syndrome is caused by 4 molecular mechanisms: [3]
    • Maternal deletions of chromosome 15q11-q13 (70-80%)
    • Intragenic mutation in maternally inherited UBE3A which is found in chromosome 15q11-q13 (10-20%)
    • Paternal uniparental disomy (UPD) in chromosome 15q11-q13 (3-5%)
    • Imprinting defects in chromosome 15q11-q13 which change the expression of UBE3A (3-5%)
  • Those with the maternal deletion have a more severe disease, while those with the mechanisms of UPD or imprinting have less severe defects [4]
  • There is typically no family history of the disease because the genetic changes are random events that occur during the formation of the reproductive cells (egg and sperm) or early in the development of the embryo. [5]
    • However, individuals with AS are capable of reproduction and in one case study with a female, it was observed that she passed the deletion on to her fetus [6]. Therefore, it may be possible to pass the gene along to offspring.
  • Life expectancy of individuals with Angelman Syndrome seems to be close to normal[5]
  • Some delayed development can be observed at 6-12 months, while other common symptoms usually occur before the age of 3 [4]

Clinical Presentation

Video created by Foundation of Angelman Syndrome (FAST), Australia

  • Observable Presentation
    • May present with facial features - thin upper lip, wide spaced teeth[4]
    • Scoliosis (20% of children; 50% adults) [7]
  • Motor Presentation[4]
    • Tremors, jerkiness, and ataxia
    • Loss of balance and wide-based gait
  • Behavioural Presentation[4]
    • Developmental delay is normally seen within the first year of life
      • most patients lack speech completely but those mildly affected can speak a few words
    • Severe intellectual disability
    • Hyperactivity and short attention span
    • Mouthing of objects
    • Happy demeanor with increased laughter, and often an attraction to water
  • Additional Comorbidities that present[4]:
    • Seizures (60% of individuals)
    • Autism spectrum disorder (ASD),
    • Digestive system complications
      • constipation
      • gastroesophageal reflux
  • Changes in Presentation with age[5]:
    • As individuals with Angelman syndrome age, they often become less excitable but continue to have intellectual disability, difficulty with speech, and seizures throughout their lives.

Diagnostic Procedures

Angelman syndrome may first be suspected in infants due to gross delay of motor milestones and/or speech delay[8]. A physiotherapist may consider a diagnosis of Angelman syndrome based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic findings. In order to confirm a suspected diagnosis, genetic testing must be completed via blood tests such as DNA methylation [4].

Differential Diagnosis

Table 1: Common Differential Diagnoses for Angelman Syndrome [9]
Differential Diagosis Key Shared Features with AS Key Distinguishing Features
Prader-Willi Syndome Developmental delays -Extreme feeding problems

-More severe behavioural symptoms such as obsessive-compulsive symptoms

Rett Syndrome Developmental delays, intellectual disability, speech impairment, seizures -Seen only in females.

-Stereotypical hand movements

-Apraxia is more severe with loss of mobility in later stages

Mowat-Wilson Syndrom Delayed motor development, intellectual disability, epilepsy -Distinct facial features

-Intestinal complications

Pitt-Hopkins Syndrome Happy disposition, speech impairments -Distinctive hand and facial features

-Self-aggression and violent outbursts


Outcome Measures

Although there are no specific outcome measures for Angelman syndrome; the following have been utilized in case-studies for assessment and to track progress:

Considering the limited literature base for physiotherapy and Angelman syndrome, physiotherapists should utilize clinical reasoning to select an outcome measure that will appropriately assess the key symptoms that their patient is experiencing.

Physiotherapy Management and Treatment

Currently there is no cure for Angelman syndrome, thus treatment focuses on symptom management. From a physiotherapy perspective, treatment focuses on the patient’s goals and follows an impairment based approach to address symptoms and comorbidities. Considering the large variability amongst individuals with Angelman Syndrome, physiotherapy treatment goals will vary across different individuals. Currently, there is limited research on physiotherapy treatment and Angelman Syndrome, as no randomized control trials exist and most evidence comes from single case-studies.Examples of treatments are as follows:

Treatments to Target Orthopedic Symptoms:

  • Encourage mobility
    • There are demonstrated benefits of mobility specific to Angelman syndrome to prevent contractures and to improve bone density. Bone density can be decreased with prolonged anti-epileptic drug treatment, so this is an important aspect to target during physiotherapy. Specifically, stationary bicycles and tricycles have shown to be effective[7]
  • Monitor for scoliosis
    • Good management of posture can help prevent or alleviate scoliosis[7]
    • A thoaco-lumbar jacket may be beneficial [2]
  • Address subluxed or pronated ankles (if present). It has been suggested that this include taping or referral for orthotics [2]

Treatment to Target Motor Skills and Balance:

  • Balance training
    • A case-study suggests using a protocol in which the patient is sitting or standing on different supports and having to perform upper-extremity functional tasks, or reacting to perturbations [11]

Treatment to Target the Cardiorespiratory System:

  • Cardiorespiratory compromise should be considered and treated in individuals who develop severe scoliosis[7].

Additional Treatment

  1. Occupational therapy:
    • Plays a key role in treating fine motor skills and self management skills to perform activities of daily living.
  2. Speech Language Pathology:
    • Plays a key role in treating difficulties with both communication and swallowing.
  3. Behavioural Therapy:
    • Plays a key role in addressing behaviour-related symptoms such as hyperactivity.

Clinical Guidelines for Angelman Syndrome

For more detailed information on the treatment of Angelman syndrome across several health care providers, clinical guidelines have been created by the Angelman Syndrome Guideline Development Group. Visit their document here: Angelman Guidelines

Clinical Bottom Line

Overall, when treating individuals with Angelman syndrome it is important to communicate with all members of their health care team, keeping in mind their intellectual and speech impairments to ensure effective communication strategies. Although individuals with Angelman syndrome do share similar symptoms, it is important to recognize that no two patients are identical and individualized therapy programs should be created.

Additional Resources

Angelman Syndrome Foundation Logo.jpg

Canadian Angelman Syndrome Society:

Angelman Syndrome Foundation:

FAST: Foundation of Angelman Syndrome Therapeutics

References

  1. Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of Angelman syndrome. Genetics in Medicine. 2010 Jul;12(7):385. doi:10.1097/GIM.0b013e3181def138
  2. 2.0 2.1 2.2 Dagli, Aditi, Jennifer Mueller, and Charles A. Williams. “Angelman Syndrome.” GeneReviews®. U.S. National Library of Medicine, 21 Dec. 2017, https://www.ncbi.nlm.nih.gov/books/NBK1144/#angelman (Accessed 5 May 2018)
  3. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nature genetics. 1997 Jan;15(1):70. doi: 10.1038/ng0197-70
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman syndrome. Neurotherapeutics. 2015 Jul 1;12(3):641-50. doi:10.1007/s13311-015-0361-y
  5. 5.0 5.1 5.2 Genetics Home Reference. Angelman Syndrome. https://ghr.nlm.nih.gov/condition/angelman-syndrome (accessed 2 May 2018)
  6. Lossie AC, Driscoll DJ. Transmission of Angelman syndrome by an affected mother. Genetics in Medicine. 1999 Sep;1(6):262. doi: 10.1097/00125817-199909000-00004
  7. 7.0 7.1 7.2 7.3 Angelman Syndrome Guideline Development Group. Management of Angelman Syndrome: A Clinical Guideline Version:1. University of Manchester, 2010. https://www.orpha.net/data/patho/Pro/en/AngelmanGuidelines2011.pdf (Accessed 2 May 2018)
  8. Williams CA, Beaudet AL, Clayton‐Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. American journal of medical genetics Part A. 2006 Mar 1;140(5):413-8. https://doi.org/10.1002/ajmg.a.31074
  9. Foundation for Angelman Syndrome Therapeutics. Common Misdiagnoses. https://cureangelman.org/understanding-angelman/differential-diagnosis. (Accessed 6 May 2018)
  10. 10.0 10.1 Kara OK, Mutlu A, Gunel MK, Haliloglu G. Do the physiotherapy results make us happy in a case with ‘happy puppet’(Angelman) syndrome?. BMJ case reports. 2010 Jan 1. doi: 10.1136/bcr.06.2010.3081
  11. 11.0 11.1 Visicato LP, Costa CS, Taube OL, Campos AC. Proposal for a physical therapy program in a child with Angelman syndrome, emphasizing postural balance: a case study. Fisioterapia e Pesquisa. 2013 Mar;20(1):70-5. http://www.scielo.br/pdf/fp/v20n1/en_12.pdf