What is the management plan for Angelman syndrome?

Management of Angelman Syndrome

Angelman syndrome requires a comprehensive multidisciplinary management approach targeting seizure control, developmental support, behavioral interventions, and monitoring for specific complications, with early diagnosis through methylation analysis being critical to implement appropriate interventions and improve quality of life. 1, 2

Diagnostic Confirmation

Before initiating management, confirm the diagnosis through appropriate genetic testing:

• Methylation analysis should be the first-line diagnostic test, detecting approximately 70% of cases with maternal deletion of 15q11-q13, plus cases due to paternal UPD (~3-5%) and imprinting defects 3, 1
• If methylation analysis shows only the paternal pattern, AS is confirmed 3
• Perform FISH with SNRPN probe and chromosome analysis to distinguish between deletion, UPD, or imprinting mutations for genetic counseling purposes 3
• If genetic testing is negative but clinical suspicion remains high (occurs in ~15-20% of cases), refer to a clinician experienced in AS or consider UBE3A gene sequencing 3, 4

Neurological Management

Seizure Control

• Epilepsy occurs in approximately 79% of patients, typically with onset in the first 4 years of life 5
• Control of epilepsy represents a major management challenge requiring ongoing adjustment of anticonvulsant therapy 5
• Monitor with EEG, as abnormal electroencephalographic background is characteristic even when seizures are controlled 2
• Expect potential improvement in seizure frequency with age, though this requires longitudinal monitoring 5

Movement Disorders

• Assess for hypermotoric and ataxic movements, which are core features of the syndrome 4, 6
• Regularly evaluate mobility status, as only 62.5% achieve independent walking (with males significantly more likely than females: 91% vs 38%) 5
• Implement appropriate physical therapy interventions based on motor function assessments 2

Developmental and Behavioral Support

Communication

• Expect absent or severely impaired speech in virtually all patients 4, 6
• Implement alternative communication strategies early, as speech will not develop through traditional approaches 2
• Utilize augmentative and alternative communication devices tailored to cognitive level 2

Behavioral Characteristics

• Recognize the characteristic behavioral phenotype including apparent happiness, paroxysms of laughter, and hyperactivity 4
• These features help distinguish AS from other severe developmental disabilities but require behavioral management strategies 4
• Address psychiatric concerns as they emerge, as behavioral issues are common 2

Multidisciplinary Care Coordination

Establish care with the following specialists:

• Neurology for seizure management and movement disorders 2
• Developmental medicine and psychology for cognitive and behavioral support 2
• Orthopedics for musculoskeletal complications and mobility optimization 2
• Ophthalmology for vision screening 2
• Sleep medicine for sleep disturbances, which are common 2
• Gastroenterology for feeding difficulties and gastrointestinal concerns 2

Monitoring and Long-term Care

• Perform regular assessments throughout the lifespan, as AS causes severe life-long disability 5
• Monitor for development of upper motor neuron signs and progression of motor dysfunction 6
• Assess caregiver health and support needs, as 21% of patients may require full-time permanent care 5
• Provide genetic counseling regarding recurrence risk, which varies by mechanism: deletions and UPD carry ~1% risk, while imprinting mutations carry up to 50% recurrence risk 7, 4

Emerging Therapies

• Multiple disease-modifying treatments are entering clinical trials, including gene replacement, enzyme replacement, and approaches targeting the paternal UBE3A gene 8
• Consider enrollment in clinical trials when appropriate, as therapeutic options are rapidly evolving 2, 8
• At least 15 different therapeutic approaches are in preclinical or clinical development, with several expected to reach clinical testing by 2022-2023 8

Critical Pitfalls to Avoid

• Do not delay diagnosis based on age; mean age of diagnosis has historically been 12.8 years, but earlier diagnosis enables earlier intervention 5
• Do not assume normal EEG rules out AS; while most have abnormal EEG, some patients have normal findings 5
• Do not overlook the diagnosis in patients with severe developmental disability, movement disorders, and absent speech—these are cardinal features requiring AS evaluation 5, 4
• Do not provide false reassurance about speech development; speech impairment is severe and persistent in AS 4, 6