Angelman Syndrome

Description of Angelman Syndrome

Angelman syndrome is a complex genetic disorder that affects the nervous system. It is characterized by severe learning difficulties, motor impairment, epilepsy, and an often happy social disposition.

Prevalence

Angelman syndrome has an estimated incidence of 1 in 12,000-20,000 live births; both males and females are affected equally [1]. Cases have been reported from all over the world, with no preference for a particular race or population [2]

Pathological Process

• Angelman syndrome is caused by 4 molecular mechanisms:[3]
  • Maternal deletion of chromosome 15q11-q13 (70-80%)
  • Intragenic mutation of maternally inherited UBE3A found on chromosome 15q11-q13 (10-20%)
  • Paternal uniparental disomy (UPD) in chromosome 15q11-q13 (3-5%)
  • Imprinting defects on chromosome 15q11-q13 alter UBE3A expression (3-5%)
• Those with a maternal deletion have a more severe form of the disease, while those with UPD or an imprinting mechanism have a less severe defect [4]
• There is usually no family history of the disorder because the genetic changes are random events that occur during the formation of germ cells (eggs and sperm) or early in embryonic development. [5]
  • However, individuals with AS are fertile and, in a case study of a female, it was observed that she passed the deletion to the fetus [6]. Therefore, it is possible to pass the gene on to offspring.
• Life expectancy for patients with Angelman syndrome appears to be near normal [5]
• Some developmental delays can be observed at 6-12 months, while other common symptoms usually occur before 3 years of age [4]

Clinical Presentation

Video produced by Foundation for Angelman Syndrome Australia (FAST)

• Facial features may be present – thin upper lip, widely spaced teeth [4]
• Scoliosis (20% of children; 50% of adults) [7]

Motor Presentation[4]:

• gait ataxia and/or
• Shaking/tremor/twitching of extremities
• Loss of balance

Behavioural Presentation[4]

• Developmental delays usually appear in the first year of life: most patients are completely unable to speak, but those who are mildly affected can speak a few words
• Severe intellectual disability
• Hyperactivity and short attention span
• Mouthing of objects
• Happy demeanor is accompanied by more laughter and is often attracted to water

Comorbidities

The individuals might present with[4]:

• Seizures (60% of individuals)
• Autism spectrum disorder (ASD),
• Digestive system complications
  • Constipation
  • Gastroesophageal reflux

Diagnostic Procedures

Angelman syndrome may first be suspected in infants due to severe delays in motor milestones and/or speech delays [8].

The diagnosis of Angelman syndrome can be based on

• a detailed patient history,
• Thorough clinical assessment and identification of characteristic findings.

To confirm a suspected diagnosis, genetic testing must be done with blood tests such as DNA methylation [4]. These tests may examine:

• Parental DNA patterns: Screening for three of the four known genetic abnormalities that cause Angelman syndrome.
• Missing chromosomes: A chromosomal microarray (CMA) shows if parts of chromosomes are missing.
• Gene mutation: If the results of the DNA methylation test are normal, your child’s doctor may order a UBE3A gene sequencing test to look for the maternal mutation.

Differential Diagnosis

Table 1: Common differential diagnoses for Angelman syndrome [9] Syndrome Developmental delay Intellectual disability Speech impairment Seizures – females only. – Stereotyped hand movements – Apraxia worse, later loss of mobility Mowat-Wilson syndrome Delayed motor development Intellectual disability Epilepsy – Distinctive facial expressions Traits – Gut Complications Pitt-Hopkins Syndrome Happy Personality Speech Impairment – Distinctive Hand and Facial Features – Self-Aggression and Violent Outbreaks

Outcome Measures

Although there are no specific outcome measures for Angelman syndrome; the following were used in the case study to assess and track progress:

• Balance:
  • Berg Balance Scale[10]
• Motor function/ performance:
  • Gross Motor Function Measure (GMFM)[10]
  • Timed up and go[11]

Given the limited literature base on physical therapy and Angelman syndrome, physical therapists should use clinical reasoning to select outcome measures that adequately assess the key symptoms a patient is experiencing.

Physiotherapy Management and Treatment

There is currently no cure for Angelman syndrome, so treatment focuses on symptom management.

From a physical therapy perspective, treatment focuses on the patient’s goals and follows an injury-based approach to address symptoms and comorbidities. Given the wide variation among individuals with Angelman syndrome, physical therapy goals will vary from person to person personal. Current research on physical therapy and Angelman syndrome is limited because no randomized controlled trials exist and most evidence comes from single case studies. Examples of treatments include:

Treatments to Target Orthopedic Symptoms

Encourage Mobility

• The flexibility characteristic of Angelman syndrome has been shown to prevent contractures and improve bone density. Long-term antiepileptic drug therapy reduces bone density, so this is an important aspect to target during physical therapy. especially stationary bikes Tricycles have proven effective[7]

Monitor for Scoliosis

• Good postural management can help prevent or alleviate scoliosis [7]
• Chest and waist jackets may be beneficial [2]
• Address the subluxed or pronated ankle (if present). It has been suggested that this includes taping or referral for orthotics [2]

Therapy for Motor Skills and Balance

Balance Training

• A case study suggested the use of a protocol in which patients sat or stood on different supports and had to perform upper extremity functional tasks or respond to perturbations [11]

Treatment for the Cardiopulmonary System

• Cardiopulmonary dysfunction should be considered and treated in individuals with severe scoliosis [7].

Additional Treatment

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

Clinical Guidelines for Angelman Syndrome

For more detailed information on the management of Angelman syndrome, the Angelman Syndrome Guideline Development Group has developed clinical guidelines for several healthcare providers. Access their documentation here: Angelman Guidelines

Clinical Bottom Line

Overall, when treating patients with Angelman syndrome, it is important to communicate with all members of their healthcare team, keeping their intellectual and language impairments in mind to ensure an effective communication strategy. Although people with Angelman syndrome do share similarities Symptoms It is important to recognize that no two patients are identical and an individualized treatment plan should be created.

Additional Resources

Canadian Angelman Syndrome Society:

• Visit their webpage here

Angelman Syndrome Foundation:

• Visit their webpage here

FAST: The Foundations of Angelman Syndrome Treatment

• Visit their webpage here

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