Angelman syndrome is a neurodevelopmental disorder originally described by Harry Angelman in the 1960s1, with an occurrence of about 1 in 12,000 births.
The most common cause of Angelman syndrome is a deletion of the maternal chromosome region 15q11-q13, which includes the UBE3A gene. Importantly, mutations and deletions of the UBE3A gene are sufficient to cause Angelman syndrome2, making UBE3A the single gene responsible for the core symptoms of the disorder. Two major deletion classes known as class I and class II deletions in the 15q11-q13 region both cause Angelman syndrome. While the loss of UBE3A causes Angelman syndrome, duplications within chromosomal regions that include UBE3A have been associated with autism3,4,5,6. Thus, a plausible relationship between a loss and duplication of UBE3A has been proposed to cause Angelman syndrome or certain types of autism, respectively.
Individuals with Angelman syndrome exhibit developmental delay, are seizure prone (roughly 90 percent of individuals), have abnormal electroencephalograms, a happy demeanor, impaired or complete lack of speech, gastrointestinal problems and ataxia 7,8.
Fly models with reductions or duplications within the Drosophila equivalent of UBE3A (dUBE3A) have been created to study behavior and identify putative UBE3A substrates 9,10. Mouse models have been generated to mimic Angelman syndrome and are being used to study behavioral, biochemical and circuit deficits, as well as to develop therapeutics for individuals with Angelman syndrome. These transgenic animals have deletions within the UBE3A gene 11,12,13.
A mouse model has also been generated to mimic the most genetically identifiable form of autism in humans: the 15q11-13 chromosomal duplication. This mouse has a large chromosomal duplication, which contains the UBE3A gene 14. To study Angelman syndrome in a way that most accurately mimics the human disorder, human induced pluripotent stem cell lines have been created from individuals with Angelman syndrome and differentiated into neurons15.
Treatments for Angelman syndrome have proven difficult, although anticonvulsants and drugs to alleviate sleep disturbances, such as melatonin, have been beneficial in some individuals with Angelman syndrome16,17,18. However, successful treatments to treat the core symptoms of Angelman syndrome have met with limited success. Multiple clinical trials are being conducted to alleviate the symptoms associated with Angelman syndrome, which include use of drugs and alterations in diet.
Relevance to autism:
Angelman syndrome has a high comorbidity with autism and shares a common genetic basis with some forms of autism. The current view states that Angelman syndrome is considered a ‘syndromic’ form of autism spectrum disorder19. Different deletion classes (class I versus class II) in Angelman syndrome have further been shown to range in the severity score for autism spectrum disorders20. This may be attributed additional genes that are deleted in Angelman syndrome individuals with a class I deletion.
- Angelman H. Dev. Med. Child Neurol. 7, 681-688 (1965) Full text
- Williams C.A. et al. Genet. Med. 12, 385-395 (2010) PubMed
- Abrahams B.S. and D.H. Geschwind Nat. Rev. Genet. 9, 341-355 (2008) PubMed
- Cook E.H. Jr. et al. Am. J. Hum. Genet. 60, 928-934 (1997) PubMed
- Browne C.E. et al. Am. J. Hum. Genet. 61, 1342-1352 (1997) PubMed
- Mao R. et al. Genet. Med. 2, 131-135 (2000) PubMed
- Bower B.D. and P.M. Jeavons Arch. Dis. Child 42, 298-302 (1967) PubMed
- Williams C.A. et al. Am. J. Med. Genet. A 140, 413-418 (2006) PubMed
- Wu Y. et al. Proc. Natl. Acad. Sci. USA 105, 12399-12404 (2008) PubMed
- Reiter L.T. et al. Hum. Mol. Genet. 15, 2825-2835 (2006) PubMed
- Ey E. et al. Autism Res. 4, 5-16 (2011) PubMed
- Mabb A.M. et al. Trends Neurosci. 34, 293-303 (2011) PubMed
- Jiang, Y.H. et al. Neuron 21, 799-811 (1998) PubMed
- Nakatani J. et al. Cell 137, 1235-1246 (2009) PubMed
- Chamberlain S.J. et al. Proc. Natl. Acad. Sci. USA 107, 17668-17673 (2010) PubMed
- Clayton-Smith J. and L. Laan J. Med. Genet. 40, 87-95 (2003) PubMed
- Braam W. et al. J. Child Neurol. 23, 649-654 (2008) PubMed
- Dion M.H. et al. Epilepsia 48, 593-596 (2007) PubMed
- Peters S.U. et al. J. Child Psychol. Psychiatry 53, 152-159 (2012) PubMed
- Peters S.U. et al. Clin. Genet. 66, 530-536 (2004) PubMed