Angelman Syndrome

Angelman Syndrome (AS) is a neurodevelopmental disorder, which is caused by mutations or deletions of the UBE3A gene inherited from the maternal allele. This gene encodes the protein E3 ubiquitin ligase. UBE3A is expressed biallelically in majority of tissues but in most neurons the maternal allele is solely expressed. In 1965 Dr. Harry Angelman an English pediatrician first described Angelman syndrome. At the time of discovery Dr. Angelman named the disorder “happy puppet syndrome” this was due to a puppet-like ataxic movement he observed in children inflicted. In the publication in which he first described AS, he stated there were certain features that he viewed in all children with the disorder. The features that Angelman stated the children

This can come about from a deletion of the critical coding region on the maternal chromosome, mutations occurring in the maternal UBE3A gene. Due to the fact that imprinting is involved in the expression of this gene, imprinting errors causing the maternal imprint to deficient. The final mechanism leading to Angelman Syndrome is due to paternal uniparental disomy (UPD). Paternal UPD occurs when an individual receives two copies of the paternal chromosomes and do not receive a maternal chromosome. The percentage of AS cases caused by each of the four mechanisms is described in the following statement, “previous studies have suggested that approximately 70% of AS individuals have deletions, 2-7% have paternal UPD, 3-5% have imprinting defects, and about 10% have mutations in maternal UBE3A”(Tan et. al, 2013). If one were to add up the aforementioned percentages they would not add up to 100%, this is due to the fact that 10% of cause do not fall into either categorizes and are still undefined. There are two classes that deletions fall under, which is exemplified by Tan et al. stating, “deletions are typically 5.9 Mb (class I) or 5.0 Mb (class II) in size, differing only by the location of the centromeric breakpoint; atypical deletions that are larger or smaller than these two common deletions have also been reported” (Tan et al, 2013). Research has shown that the clinical

A group wanted to test how mutations influence features in early childhood, in respect of Angelman Syndrome. They gathered data from 92 children presenting with AS from the age of five to six months. The factors that differed between the children were based on the mechanism leading to the onset of the disorder, “Seventy-four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations” (Tan et al, 2013). This genotype-phenotype correlation was implored to gain further insight into the disease. The findings of this study showed a correlation between an increased weight/obesity found in individuals with UPD/imprinting defects. This held true even though there was the issue with feeding at an early age in majority of the children. This led the authors to begin to draw a correlation with Prader-Willie Syndrome. Individuals suffering from Prader-Willie Syndrome are missing the same gene located at the same locus but in these individuals it is found on the paternal copy of chromosome #15. This led the researches to question why this correlation existed because in individuals with two copies of paternal chromosome #15 the over expression of UBE3A seem to be a cause. The issue is in Prader-Willie Syndrome that paternal chromosome is not expressed. This led the researchers to