Angelman Syndrome

Abstract

Angelman syndrome (AS) is characterized by severe developmental delays, movement or balance disorders, a happy demeanor, and speech impairment. Other features may include microcephaly, seizures, EEG abnormalities, feeding problems, chewing/mouthing, uplifted flexed arm position, wide-based gait, and abnormal sleep cycles. Standard treatments include medications for seizures or sleep problems, physical therapy, and speech therapy. Deficits in maternal chromosome 15q11.2-13, containing the UBE3A allele, result in AS. Mechanisms include UBE3A deletion, uniparental disomy, imprinting center defects, UBEUBE3A3A mutations. Diagnostic testing involves methylation studies of chromosome 15q11-q13 with possible subsequent microsatellite, FISH analysis, or microarray study to confirm the specific cause of AS or UBEUBE3A3A gene mutation testing. If testing is negative, consensus criteria may be used for diagnosis. Current targeted treatments being studied include topoisomerase inhibitors, which increased paternal expression of UbeUbe3a3a in animal models of AS, but have not yet undergone trials in humans. Minocycline, a semi-synthetic tetracycline derivative, improved motor coordination, cognition and hippocampal synaptic function in animal models of AS, and a trial in humans with AS is currently underway. Promethylation dietary supplements have been theorized to increase DNA methylation and activate the paternally inherited UBE3A allele. However, double-blind, placebo-controlled trials with folic acid and betaine in individuals with AS have not shown any treatment benefits. Levodopa, a dopamine agonist used in Parkinson disease, is a potential therapy as AS mice lacking the maternal ube3a have reduced dopamine cell numbers in the substantia nigra, and a trial of levodopa/carbidopa in children with AS is ongoing.