Angelman syndrome is clinically characterized by a severe developmental delay with language being much more affected than motor function. Early signs and symptoms are inconstant visual fixation, insecure grasping, and muscular hypotonia. Later on, gait ataxia, frequent drooling, increased oral exploration of objects as well as hand automatisms may be present. Many children develop epilepsy with characteristic EEG patterns. Physical features frequently include microcephaly, midfacial hypoplasia with mandibular prognathism and a wide mouth; in patients with microdeletion (see below) frequently also hypopigmentation. Many affected patients are only able to use few words but show higher receptive and non-verbal communication skills and can therefore communicate better via gestures and sign language. A balanced, friendly personality is typical for the Angelman syndrome. Some patients show frequent episodes of laughter, sometimes even under the influence of inadequate stimuli like pain. Congenital malformations are rare, thus life expectancy does not seem to be restricted significantly. The prevalence of Angelman syndrome is considered to be 1:10,000–1:20,000.
The genes causal for Angelman syndrome and Prader-Willi syndrome (PWS) are located in a chromosomal region (15q11.2–q13) that is subject to genomic imprinting. This parent-specific imprinting causes the genes to differ in the degree of DNA methylation, the chromatin structure, and thus in the expression, depending on what parent they are originating from. It is controlled by an imprinting center in 15q11.2–q13, consisting of two parts. Due to this special feature PWS and AS can have other causes besides the microdeletion that lead to loss of expression of the specific genes. The only gene associated with causing AS so far is UBE3A, which is expressed in the brain exclusively by the maternal chromosome 15.
Approximately 70% of AS patients have a microdeletion 15q11.2–q13 on the maternally inherited chromosome 15. Around 1% have a paternal uniparental disomy (UPD) of chromosome 15, i.e. both chromosomes 15 originate from the father, none from the mother. Approximately 4% show a defect in the imprinting center and approximately 5% have a mutation in the UBE3A gene. In 20% of patients diagnosed with AS the genetic cause cannot be found with the current diagnostic methods. Microdeletion and UPD bear a small risk of recurrence; mutations in the imprinting center and UBE3A mutations may be inherited with a risk of up to 50%.
Cytogenetic (FISH) analysis covers only the microdeletion, methylation-sensitive PCR covers microdeletion, UPD and imprinting mutation without specification.