This can be due to genetic errors such as the deletion or mutation of a segment of chromosome 15, uniparental disomy, or translocation. While Angelman syndrome can be caused by a single mutation in the UBE3A gene, the most common genetic defect leading to Angelman syndrome is a 5- to 7-Mb (megabase) maternal deletion in chromosomal region 15q11.2-q13.Specifically, the paternal copy of UBE3A is known to be imprinted within the hippocampus, cortex, thalamus, olfactory bulb, and cerebellum. Therefore, in these areas of the brain, a functioning maternal copy of UBE3A is essential for proper development.Region 15q11-13 is implicated in both Angelman syndrome and Prader–Willi syndrome (PWS). While AS results from mutation, loss or abnormal imprinting involving the UBE3A gene within this region on the maternal chromosome, loss of a different cluster of genes within the same region on the paternal chromosome causes PWS.The methylation test that is performed for Angelman syndrome looks for methylation on the genes neighbor SNRPN, which is silenced by methylation on the maternal copy of the gene. Neurophysiology
The electroencephalogram (EEG) in AS is usually abnormal, more so than clinically expected. This EEG facilitates the differential diagnosis of AS, but is not pathognomonic. Three distinct interictal patterns are seen in these patients. The most common pattern is a very large amplitude 2–3 Hz rhythm most prominent in prefrontal leads. Next most common is a symmetrical 4–6 Hz high voltage rhythm. The third pattern, 3–6 Hz activity punctuated by spikes and sharp waves in occipital leads, is associated with eye closure.
Paroxysms of laughter have no relation to the EEG, ruling out this feature as a gelastic phenomenon.EEG anomalies may be used as a quantitative biomarkers to "chart progression of AS and as clinical outcome measures". Slow delta activity (~3 Hz) is greatly increased in AS relative to typically developing children, yet more pronounced in children with partial 15q deletions as opposed to those with etiologies principally affecting UBE3A. Theta activity (~5 Hz) is much greater in children with partial 15q deletions. Thus, delta activity appears to be chiefly reflective of UBE3A dysfunction with some modulation from other 15q genes, whereas theta activity may be an electrophysiological readout of genes beyond UBE3A such as GABRA5, GABRB3, and GABRG3. Future clinical trials in AS might exploit the foregoing by using EEG as a readout of drug target engagement.It appears that the neurons of people with Angelman syndrome are formed correctly, but they cannot function properly. Diagnosis
The diagnosis of Angelman syndrome is based on:
A history of delayed motor milestones and then later a delay in general development, especially of speech
Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-legged gait. Characteristic facial appearance (but not in all cases). A history of epilepsy and an abnormal EEG tracing.