Angelman syndrome

Angelman syndrome is a neurodevelopmental condition that primarily affects the brain and nervous system, leading to significant challenges with learning, movement, and communication. It results when the maternal copy of the UBE3A gene is inactive or missing, leaving neurons without enough of the UBE3A protein that helps regulate other proteins within the cell. Signs usually become apparent in infancy or early childhood, and the condition affects males and females equally. Angelman syndrome is considered uncommon, occurring in roughly 1 in 12,000 to 20,000 births worldwide. Severity and symptoms vary widely between individuals.

A distinctive, happy demeanor with frequent smiling, laughter, and hand-flapping movements is often what first alerts families and clinicians. Early in infancy, low muscle tone and feeding difficulties may be noticed, followed by clear delays in sitting, crawling, and walking. Many children eventually develop a wide-based, ataxic gait and tremor. Neurological features dominate the clinical picture. Nearly all individuals have severe global developmental delay and intellectual disability, and most have absent or minimal spoken language. Epilepsy is common and may begin before three years of age, with electroencephalogram patterns that show high-amplitude slow waves. Sleep disturbance, hyperactivity, and autistic or other atypical behaviors are frequently reported. Microcephaly often becomes apparent over time. Additional findings can include fascination with water, hypopigmentation of skin or hair (especially when a chromosomal deletion is present), constipation, and self-injurious behavior. Not all individuals experience every feature, and the clinical spectrum ranges from mild motor involvement to complex medical needs requiring substantial support.

Angelman syndrome involves genomic imprinting, a parent-of-origin phenomenon in which only the maternal copy of the UBE3A gene is active in neurons. Loss of functional maternal UBE3A can occur through several mechanisms: approximately 70 percent of affected individuals have a deletion of the maternal 15q11-q13 region, about 2 percent have paternal uniparental disomy (both chromosome 15s come from the father), roughly 3 percent have an imprinting defect that disrupts normal maternal gene activation, and around 10 percent have a disease-causing sequence variant within the maternal UBE3A gene itself. Most cases arise as new (de novo) events, although the underlying mechanism determines whether the chance of recurrence in a family is very low or higher. Because inheritance and recurrence risks differ by mechanism, families are encouraged to meet with a genetic counselor when planning future pregnancies. An individual with Angelman syndrome can transmit a pathogenic UBE3A variant to offspring, and the outcome will depend on whether the altered gene is inherited from the mother or father.

Currently, management focuses on supportive care and symptom control, delivered through a multidisciplinary team that may include neurologists, developmental pediatricians, speech-language pathologists, physical and occupational therapists, behavioral specialists, and genetic counselors. Seizure management often requires more than one antiepileptic medication, and treatment choices are tailored to seizure type and individual tolerance. Regular surveillance is an essential part of long-term care, helping to identify potential complications such as worsening epilepsy or sleep disturbances before they become serious. Foundational therapies play a central role. Physical therapy promotes motor skills and reduces gait difficulties, while occupational therapy builds daily living abilities. Speech therapy, including augmentative and alternative communication devices, supports expressive language. Behavioral interventions address sleep issues, hyperactivity, and self-injurious behaviors. Family education about safety around water and strategies for managing hyperexcitability is also important. Although no treatments are specifically approved for Angelman syndrome at this time, several gene-targeted or UBE3A-reactivation strategies are being evaluated in clinical trials. Eligibility for these investigational therapies depends on individual factors and should be discussed with the care team.

Angelman syndrome is a lifelong condition. Many individuals learn to walk, communicate through alternative methods, and participate in family and community life with appropriate supports. Outcomes vary depending on seizure control, degree of motor impairment, and access to early interventions. While most people require ongoing assistance with daily activities, many live into adulthood and continue to make developmental gains at their own pace. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialized clinics, patient advocacy groups, and genetic counselors, who can guide them toward therapies, educational resources, and community support.

Angelman syndrome is an active area of investigation, with several clinical trials currently exploring therapy approaches such as unsilencing the paternal UBE3A gene by antisense oligonucleotides, gene transfer techniques, and other molecular strategies. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility. Continued participation in natural history studies and disease registries helps researchers understand long-term outcomes and accelerates therapeutic development.