Angelman Syndrome

Genetics

Caused by loss of function of the maternally expressed UBE3A allele in neurons. Mechanisms include maternal 15q11.2-q13 deletion, a pathogenic UBE3A variant, paternal uniparental disomy or an imprinting defect; recurrence risk depends on the molecular class.

Molecular Mechanism

Loss of neuronal UBE3A E3 ubiquitin-ligase activity disrupts protein homeostasis, synaptic maturation and plasticity. The normally intact paternal allele is silenced in neurons by the UBE3A antisense transcript, creating a therapeutic opportunity for paternal-allele reactivation.

Therapy

Current care is symptomatic, including seizure control, sleep management and intensive communication, physical and occupational support. Antisense oligonucleotides targeting UBE3A-ATS, gene replacement and other UBE3A reactivation strategies are in clinical development, but no disease-modifying therapy is yet approved.

CCP Activity

CCP characterizes complementary Angelman models and develops epigenetic modifying gene therapies to restore neuronal UBE3A expression.