Introduction

Overview

Angelman Syndrome

Demographics

• Incidence: Estimated between 1 in 12,000 and 1 in 20,000 live births.
• Prevalence: Approximately 500,000 individuals worldwide. In the USA, there are around 10,373 addressable cases.
• Gender Distribution: Affects males and females equally.
• Typical Age of Onset: Typically noticeable between 6 and 12 months of age, with developmental delays becoming more apparent over time.

Coding

• ICD-11: 8A07.2
• ICD-10-CM: Q93.51
• OMIM: 105830
• UMLS: C0002573
• MeSH: D018139
• GARD: 110

Overview

Angelman syndrome (AS) is a rare neurogenetic disorder characterized by intellectual disability, severe speech impairment, ataxia, seizures, and a distinct behavioral phenotype marked by frequent laughter and a happy demeanor. It is caused by the loss of function or abnormal expression of the UBE3A gene on chromosome 15, which is inherited from the mother.

AS often presents with additional neurological and physical findings, including:

• Microcephaly: An unusually small head size.
• Feeding difficulties: Difficulty coordinating sucking and swallowing.
• Hypotonia: Decreased muscle tone.
• Strabismus: Misalignment of the eyes.
• Hypopigmentation: Lighter than typical skin, hair, and eye color, more noticeable if the individual has a mixed racial background.

These characteristics contribute to a range of developmental and neurological challenges, including:

• Profound developmental delays: Most individuals with AS never learn to speak or walk independently.
• Intellectual disability: Requiring lifelong support.
• Sleep disturbances: Difficulty falling asleep and staying asleep.

Medical Features and Pathophysiology

Pathophysiology

• Genetic Basis: AS is primarily caused by the loss of function of the UBE3A gene on chromosome 15, which is maternally inherited. This gene provides instructions for making a protein (ubiquitin protein ligase E3A) that plays a crucial role in the development and function of the nervous system.
• Loss of Function: In AS, the maternal copy of the UBE3A gene is either mutated or deleted, resulting in a deficiency or absence of functional ubiquitin protein ligase E3A in neurons.
• Impact on Brain Regions: This loss of UBE3A gene function leads to an imbalance in specific proteins involved in neuronal signaling, synaptic plasticity (the ability of synapses to strengthen or weaken over time), and brain development. This disruption affects various brain regions, particularly the hippocampus (involved in learning and memory), cerebellum (responsible for motor control and coordination), and cerebral cortex (responsible for higher-level cognitive functions).

Symptoms

Early Signs (0-12 Months)

• Developmental Delays: Delays in reaching milestones like sitting, crawling, and babbling may be subtle initially.
• Feeding Difficulties: Problems with sucking, swallowing, and coordinating feeding can be early signs.
• Hypotonia: Reduced muscle tone, often noticeable as "floppiness."
• Lack of Eye Contact: May be less responsive to social cues.

Later Symptoms (12 Months and Beyond)

• Severe Speech Impairment: Most individuals with AS never develop functional speech.
• Gait Abnormalities: Ataxia (unsteady gait) is common, and many individuals never walk independently. May also have jerky movements or tremors.
• Seizures: Seizures, often difficult to control with medication, are common.
• Sleep Disturbances: Frequent nighttime awakenings and daytime sleepiness are common.
• Behavioral Characteristics: Individuals with AS often display a happy demeanor, frequent laughter or smiling, hyperactivity, a short attention span, and fascination with water.

Diagnosis

• Clinical Evaluation: Diagnosis is based on a thorough review of the child's medical history, physical examination, and observation of developmental milestones and characteristic features.
• Genetic Testing: Genetic testing is essential to confirm the diagnosis and identify the specific genetic mechanism underlying AS. The most common test is a methylation analysis, which can detect the absence of the maternal UBE3A gene expression. Other tests, such as chromosomal microarray or gene sequencing, may be used to identify deletions or mutations in the UBE3A gene.

Management and Treatment

There is no cure for AS, but various therapies and interventions can help manage symptoms, improve quality of life, and support development.

Medications

• Anticonvulsants: To manage seizures.
• Sleep Medications: To improve sleep patterns.
• Medications for Gastrointestinal Issues: To address feeding difficulties, reflux, or constipation.

Therapies

• Physical Therapy: To improve muscle strength, coordination, balance, and gross motor skills. Therapists may recommend adaptive equipment, such as standers or gait trainers, to promote mobility.
• Occupational Therapy: To enhance fine motor skills, hand-eye coordination, and adaptive skills for daily living. Therapists may focus on activities that promote hand use, such as grasping and releasing objects, and may recommend adaptive equipment to assist with feeding, dressing, and other self-care tasks.
• Speech-Language Therapy: To address communication challenges. Because most individuals with AS have severe speech impairment, therapists focus on alternative and augmentative communication (AAC) methods, such as sign language, picture exchange systems, or speech-generating devices.
• Behavioral Therapy: To address challenging behaviors and promote positive social interactions. Applied Behavior Analysis (ABA) is a commonly used approach that focuses on reinforcing desired behaviors and reducing problematic ones.

Assistive Technology and Communication Devices

Assistive technology plays a crucial role in enhancing communication, learning, and independence for individuals with AS. Given the severe developmental delays and physical disabilities associated with AS, a significant percentage may require assistive technology.

Speech Generating Devices (SGDs)

SGDs are particularly important for individuals with AS due to their severe speech impairment. These devices range from simple to highly sophisticated:

• Low-tech Options:

- Communication boards with symbols or photos

• High-tech Options:

- Dedicated SGDs (e.g., Tobii Dynavox devices)

Importance of Symbols for Individuals with AS

Symbols are an essential component of AAC systems for individuals with AS due to several factors:

• Cognitive and Linguistic Challenges: Most individuals with AS have significant cognitive impairments and limited or no verbal language skills. Symbols provide a more concrete and accessible way to represent language concepts compared to abstract text.
• Visual Processing Strengths: Individuals with AS may demonstrate relative strengths in visual processing compared to auditory processing. Visual symbols capitalize on these strengths to support communication.
• Developmental Appropriateness: Symbols, particularly those that closely resemble real objects or actions, align with the developmental level of most individuals with AS. They provide a more natural starting point for communication development compared to text.

Assessment and Selection of Symbol Sets

A comprehensive AAC assessment is essential to determine the most appropriate symbol set for an individual with AS. Key considerations include:

• Symbolic Understanding: Assess the individual's ability to understand and use various types of symbols, from simple, concrete representations to more abstract concepts.
• Visual Skills: Consider the individual's visual acuity, visual field, and visual perceptual skills when selecting symbols. Individuals with significant visual impairments may require larger, higher-contrast symbols or even tactile symbols.
• Motor Skills: Evaluate the individual's ability to accurately select symbols given their motor abilities. Symbols may need to be spaced farther apart or presented in a linear layout to accommodate motor challenges.
• Customization: Be prepared to customize symbol sets to reflect an individual's specific needs, interests, and environment. Personal photos, for example, can be highly meaningful and motivating.

Access Methods

The choice of access method is critical and depends on the individual's motor abilities, which are often significantly impaired in AS:

• Direct Selection:

- Key guards or enlarged buttons can be helpful for those with less precise movements, which is common in AS.

• Scanning:

- Two-switch step scanning may be possible for some individuals with better motor control, but is less common in AS.

• Eye Gaze Technology:

- It requires consistent eye control and the ability to fixate gaze, which may be challenging for some individuals with AS due to attention deficits or visual processing issues.

• Head-Tracking Systems:

Literacy Considerations

While many individuals with AS may not develop traditional literacy skills, it is essential to provide opportunities for literacy development within their AAC systems:

• Exposure to Print: Consistently pairing symbols with printed words can help build print awareness and recognition over time.
• Sight Words: Some individuals with AS may develop sight word recognition. Incorporating personally meaningful sight words into an AAC system can enhance communication efficiency.

Customization and Implementation

• Personalized Vocabulary Selection: Choose vocabulary that is meaningful and relevant to the individual's daily life, interests, and communication needs.
• Consistency Across Environments: Ensuring the same communication system is used at home, school, and in therapy settings promotes generalization of skills.
• Training for Communication Partners: Family members, caregivers, and educators need extensive training to effectively support and respond to the individual's communication attempts, especially given the unique behavioral profile of AS.

Behavioral Considerations

• Attention Span: Many individuals with AS have short attention spans, so communication systems should be engaging and easy to navigate.
• Hyperactivity: Devices should be durable and securely mounted to withstand potential rough handling.
• Motivation: Incorporating highly motivating vocabulary and activities can increase engagement with the communication system.

Considerations for Visual Impairment

For individuals with AS who also have visual impairments:

• Tactile Symbols: Raised or textured symbols can provide additional sensory input.
• Auditory Scanning: SGDs can be set to speak options aloud for selection.
• Enlarged Displays: Increasing symbol size and enhancing contrast can aid those with low vision.

Care Management and Therapeutic Techniques

Managing Angelman syndrome requires a comprehensive, multidisciplinary approach involving healthcare professionals, educators, therapists, and families.

Aims

• Maximize the individual's potential in all areas of development.
• Manage medical and behavioral challenges effectively.
• Enhance communication and social interaction.
• Promote independence and improve quality of life.
• Support family functioning and well-being.

Medical Management

• Regular medical check-ups to monitor growth, development, and overall health.
• Seizure management with appropriate medication and monitoring.
• Treatment of any associated medical conditions (e.g., gastrointestinal issues, sleep disorders).

Behavioral and Psychological Support

• Behavioral therapy to address challenging behaviors and develop coping mechanisms.
• Positive reinforcement strategies to encourage desired behaviors.
• Structured routines and environments to promote predictability and reduce anxiety.

Therapies and Interventions

• Physical Therapy: To improve muscle strength, coordination, balance, and gross motor skills. Therapists may recommend adaptive equipment, such as standers or gait trainers, to promote mobility.
• Occupational Therapy: To enhance fine motor skills, hand-eye coordination, and adaptive skills for daily living. Therapists may focus on activities that promote hand use, such as grasping and releasing objects, and may recommend adaptive equipment to assist with feeding, dressing, and other self-care tasks.
• Speech-Language Therapy: To address communication challenges. Because most individuals with AS have severe speech impairment, therapists focus on alternative and augmentative communication (AAC) methods, such as sign language, picture exchange systems, or speech-generating devices.
• Behavioral Therapy: To address challenging behaviors and promote positive social interactions. Applied Behavior Analysis (ABA) is a commonly used approach that focuses on reinforcing desired behaviors and reducing problematic ones.
• Music Therapy: To promote engagement, communication, and emotional expression.

Educational Strategies

• Individualized Education Program (IEP): Children with AS are entitled to a free and appropriate public education (FAPE) tailored to their unique needs. An IEP outlines specific learning goals, support services, and accommodations to help the child access the curriculum.
• Special Education Services: Depending on the severity of their disabilities, children with AS may benefit from placement in a special education classroom or receive support services within a general education setting.
• Visual Supports: Visual schedules, social stories, and picture cards can aid comprehension, reduce anxiety, and promote independence.

Family and Community Support

• Genetic Counseling: Genetic counseling can help families understand the inheritance pattern of AS, recurrence risks, and available testing options.
• Support Groups: Connecting with other families affected by AS can provide emotional support, practical advice, and a sense of community.
• Respite Care: Respite care services can provide temporary relief for caregivers, allowing them to take breaks, attend appointments, or simply recharge.

Challenges and Considerations

Medical Complexity

Managing multiple health issues, including seizures, sleep disorders, and gastrointestinal problems, requires coordinated care from various specialists.

Communication Barriers

Severe speech impairment necessitates the use of alternative communication strategies, which can be challenging to implement and require consistent effort from communication partners.

Behavioral Challenges

Hyperactivity, short attention span, and sometimes challenging behaviors can impact daily life, learning, and social interactions.

Long-term Care

Most individuals with AS require lifelong support and supervision, placing significant demands on families and caregivers.

Extended Information

Pathological Insights

• Research suggests that the loss of UBE3A function disrupts the balance of excitatory and inhibitory signaling in the brain, potentially contributing to seizures, hyperactivity, and learning difficulties.
• Studies are ongoing to further elucidate the precise cellular and molecular mechanisms underlying AS and to identify potential therapeutic targets.

Genetic and Environmental Factors

• The vast majority of AS cases are caused by genetic mutations or deletions affecting the maternal copy of the UBE3A gene.
• In rare cases, AS can result from paternal uniparental disomy (both copies of chromosome 15 are inherited from the father), imprinting defects (where the maternal UBE3A gene is silenced), or mutations in other genes involved in the ubiquitin-proteasome system.
• While environmental factors are not believed to directly cause AS, they can influence the severity of symptoms or the individual's response to interventions.

Clinical Presentation and Disease Progression

• The clinical presentation of AS can vary widely, even among individuals with the same genetic abnormality.
• Symptoms typically emerge during infancy, with developmental delays becoming more apparent over time.
• While there is no cure for AS, early intervention and ongoing therapies can significantly improve outcomes and quality of life.

Current Research and Future Directions

• Current research on AS is focused on developing targeted therapies to address the underlying genetic defect, such as gene therapy approaches to replace or activate the maternal UBE3A gene.
• Other areas of research include investigating the use of medications to improve specific symptoms, such as seizures or sleep disturbances, and exploring novel therapeutic approaches, such as deep brain stimulation.

Support and Resources

• Angelman Syndrome Foundation: https://www.angelman.org/
• National Organization for Rare Disorders (NORD): https://rarediseases.org/
• Genetic and Rare Diseases Information Center (GARD): https://rarediseases.info.nih.gov/
• MedlinePlus: https://medlineplus.gov/
• MedlinePlus Genetics: https://medlineplus.gov/genetics/
• Facebook Support Group: Angelman Syndrome Support Group
• Twitter Community: #AngelmanSyndrome
• Reddit Community: r/AngelmanSyndrome
• Instagram Awareness Page: @angelmansyndromeawareness
• YouTube Channel: Angelman Syndrome Stories

References

1. Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140(5):413-418. 2. Tan WH, Bird LM, Thibert RL, et al. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A. 2014;164A(4):975-992. 3. Buiting K, Williams C, Horsthemke B. Angelman syndrome - insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016;12(10):584-593. 4. Dagli AI, Williams CA. Angelman Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. 5. Thibert RL, Larson AM, Hsieh DT, et al. Neurologic manifestations of Angelman syndrome. Pediatr Neurol. 2013;48(4):271-279. 6. Pelc K, Boyd SG, Cheron G, et al. Epilepsy in Angelman syndrome. Seizure. 2008;17(3):211-217. 7. Tan WH, Bacino CA, Skinner SA, et al. Angelman syndrome: Mutations influence features in early childhood. Am J Med Genet A. 2011;155A(1):81-90. 8. Larson AM, Shinnick JE, Shaaya EA, et al. Angelman syndrome in adulthood. Am J Med Genet A. 2015;167A(2):331-344. 9. Sadhwani A, Wheeler AC, Bird LM, et al. Developmental trajectory and genotype-phenotype correlations in Angel

Epidemiology and Demographics

Etiology and Pathophysiology

Clinical Features and Stages

Diagnosis

Clinical Recommendations

Care Management

Transition Planning