Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Angelman syndrome — insights into a rare neurogenetic disorder

Nature Reviews Neurology volume 12, pages 584–593 (2016)Cite this article

Subjects

Key Points

  • Angelman syndrome is a rare neurogenetic disorder characterized by microcephaly, seizures, ataxia, muscular hypotonia with hyperreflexia, and motor delay

  • Angelman syndrome is caused by deficiency of ubiquitin–protein ligase 3A gene (UBE3A) in the CNS

  • UBE3A deficiency impairs synapse formation and experience-dependent synapse remodelling

  • In neurons, the paternal UBE3A allele is silenced by a paternally expressed antisense transcript, so that only the maternal UBE3A allele is expressed

  • Novel therapeutic approaches are aimed at activating the silent paternal UBE3A allele

  • Translational research in rare diseases such as Angelman syndrome requires international collaborations between researchers, clinicians, caregivers, and parent and patient support groups

Abstract

Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin–protein ligase E3A) gene on chromosome 15q11.2–q13. This loss of function can be caused by a mutation on the maternal allele, a 5–7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect. The chromosomal deletion tends to cause the most severe symptoms, possibly owing to co-deletion of GABA receptor genes. UBE3A mutations and imprinting defects can be associated with a high risk of recurrence within families. Disruption of UBE3A function in neurons seems to inhibit synapse formation and experience-dependent synapse remodelling. Clinical diagnosis of Angelman syndrome in infants and young children is sometimes difficult, but can be verified by genetic tests. At present, treatment of symptoms such as seizures is the only medical strategy, but genetic therapies aimed at activating the silent copy of UBE3A on the paternal allele are conceivable.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Individuals with Angelman syndrome.
Figure 2: Chromosomal region 15q11.2–q13.
Figure 3: Transcriptional interference at the UBE3A locus in neurons.
Figure 4: Familial segregation of an imprinting centre deletion.
Figure 5: Synapse formation and remodelling in Angelman syndrome.

Similar content being viewed by others

References

  1. Buiting, K. et al. Clinical utility gene card for: Angelman syndrome. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2014.93 (2015).

  2. Angelman, H. 'Puppet' children. A report of three cases. Dev. Med. Child Neurol. 7, 681–688 (1965).

    Article  Google Scholar 

  3. Magenis, R. E., Brown, M. G., Lacy, D. A., Budden, S. & LaFranchi, S. Is Angelman syndrome an alternate result of del(15)(q11q13)? Am. J. Med. Genet. 28, 829–838 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Kaplan, L. C. et al. Clinical heterogeneity associated with deletions in the long arm of chromosome 15: report of 3 new cases and their possible genetic significance. Am. J. Med. Genet. 28, 45–53 (1987).

    Article  CAS  PubMed  Google Scholar 

  5. Donlon, T. A. Similar molecular deletions on chromosome 15q11.2 are encountered in both the Prader–Willi and Angelman syndromes. Hum. Genet. 80, 322–328 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Knoll, J. H. et al. Angelman and Prader–Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am. J. Med. Genet. 32, 285–290 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Butler, M. G. & Palmer, C. G. Parental origin of chromosome 15 deletion in Prader–Willi syndrome. Lancet 1, 1285–1286 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Malcolm, S. et al. Uniparental paternal disomy in Angelman's syndrome. Lancet 337, 694–697 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Vu, T. H. & Hoffman, A. R. Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat. Genet. 17, 12–13 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat. Genet. 15, 70–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Matsuura, T. et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet. 15, 74–77 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Williams, C. A. et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am. J. Med. Genet. A 140A, 413–418 (2006).

    Article  Google Scholar 

  13. Ramsden, S. C., Clayton-Smith, J., Birch, R. & Buiting, K. Practice guidelines for the molecular analysis of Prader–Willi and Angelman syndromes. BMC Med. Genet. 11, 70 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tan, W. H. et al. Angelman syndrome: mutations influence features in early childhood. Am. J. Med. Genet. A 155A, 81–90 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Muñoz-Cabello, B. et al. [Epileptic seizures in Angelman syndrome]. Rev. Neurol. 47, 113–118 (in Spanish) (2008).

    PubMed  Google Scholar 

  16. Fiumara, A., Pittalà, A., Cocuzza, M. & Sorge, G. Epilepsy in patients with Angelman syndrome. Ital. J. Pediatr. 36, 31 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Galvan-Manso, M., Campistol, J., Conill, J. & Sanmarti, F. X. Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome. Epileptic Disord. 7, 19–25 (2005).

    PubMed  Google Scholar 

  18. Ogawa, K., Othsuka, Y., Kobayashi, K., Asano, T. & Oka, E. The characteristics of epilepsy with Angelman syndrome. Epilepsia 37 (Suppl. 3), 83–84 (1996).

    Article  Google Scholar 

  19. Pelc, K., Boyd, S. G., Cheron, G. & Dan, B. Epilepsy in Angelman syndrome. Seizure 17, 211–217 (2008).

    Article  PubMed  Google Scholar 

  20. Thibert, R. L. et al. Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia 50, 2369–2376 (2009).

    Article  PubMed  Google Scholar 

  21. Harting, I. et al. Abnormal myelination in Angelman syndrome. Eur. J. Paediatr. Neurol. 13, 271–276 (2009).

    Article  PubMed  Google Scholar 

  22. Wilson, B. J. et al. Abnormal language pathway in children with Angelman syndrome. Pediatr. Neurol. 44, 350–356 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jay, V., Becker, L. E., Chan, F. W. & Perry, T. L. Sr. Puppet-like syndrome of Angelman: a pathologic and neurochemical study. Neurology 41, 416–422 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Zori, R., Williams, C., Mattei, J. F. & Moncla, A. Parental origin of del(15)(q11–q13) in Angelman and Prader–Willi syndromes. Am. J. Med. Genet. 37, 294–295 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Williams, C. A. The behavioral phenotype of the Angelman syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 154C, 432–437 (2010).

    Article  PubMed  Google Scholar 

  26. Jolleff, N. & Ryan, M. M. Communication development in Angelman's syndrome. Arch. Dis. Child. 69, 148–150 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Penner, K. A., Johnston, J., Faircloth, B. H., Irish, P. & Williams, C. A. Communication, cognition, and social interaction in the Angelman syndrome. Am. J. Med. Genet. 46, 34–39 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Alvares, R. & Downing, S. A survey of expressive communication skills in children with Angelman syndrome. Am. J. Speech Lang. Path. 7, 14–24 (1998).

    Article  Google Scholar 

  29. Williams, C. A. et al. Angelman syndrome: consensus for diagnostic criteria. Am. J. Med. Genet. 56, 237–238 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Larson, A. M., Shinnick, J. E., Shaaya, E. A., Thiele, E. A. & Thibert, R. L. Angelman syndrome in adulthood. Am. J. Med. Genet. A 167A, 331–344 (2015).

    Article  PubMed  Google Scholar 

  31. Clayton-Smith, J. Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev. Med. Child Neurol. 43, 467–480 (2001).

    Article  Google Scholar 

  32. Laan, L. A., den Boer, A. T., Hennekam, R. C., Renier, W. O. & Brouwer, O. F. Angelman syndrome in adulthood. Am. J. Med. Genet. 66, 356–360 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Yamamoto, Y., Huibregtse, J. M. & Howley, P. M. The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing. Genomics 41, 263–266 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Kishino, T. & Wagstaff, J. Genomic organization of the UBE3A/E6-AP gene and related pseudogenes. Genomics 47, 101–107 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Buiting, K. et al. Inherited microdeletions in the Angelman and Prader–Willi syndromes define an imprinting centre on human chromosome 15. Nat. Genet. 9, 395–400 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Sutcliffe, J. S. et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat. Genet. 8, 52–58 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Rougeulle, C., Cardoso, C., Fontés, M., Colleaux, L. & Lalande, M. An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript. Nat. Genet. 19, 15–16 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Runte, M. et al. The IC-SNURF–SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Mol. Genet. 10, 2687–2700 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Meng, L., Person, R. E. & Beaudet, A. L. Ube3a–ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Hum. Mol. Genet. 21, 3001–3012 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Meng, L. et al. Truncation of Ube3a–ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model. PLoS Genet. 9, e1004039 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. LaSalle, J. M., Reiter, L. T. & Chamberlain, S. J. Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. Epigenomics 7, 1213–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Runte, M. et al. SNURF–SNRPN and UBE3A transcript levels in patients with Angelman syndrome. Hum. Genet. 114, 553–561 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Numata, K., Kohama, C., Abe, K. & Kiyosawa, H. Highly parallel SNP genotyping reveals high-resolution landscape of mono-allelic Ube3a expression associated with locus-wide antisense transcription. Nucleic Acids Res. 39, 2649–2657 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Knoll, J. H. et al. Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. Am. J. Hum. Genet. 47, 149–155 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Amos-Landgraf, J. M. et al. Chromosome breakage in the Prader–Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65, 370–386 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Christian, S. L., Fantes, J. A., Mewborn, S. K., Huang, B. & Ledbetter, D. H. Large genomic duplicons map to sites of instability in the Prader–Willi/Angelman syndrome chromosome region (15q11–q13). Hum. Mol. Genet. 8, 1025–1037 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Sahoo, T. et al. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype–phenotype correlations. Eur. J. Hum. Genet. 15, 943–949 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Dagli, A., Buiting, K. & Williams, C. A. Molecular and clinical aspects of Angelman syndrome. Mol. Syndromol. 2, 100–112 (2012).

    CAS  PubMed  Google Scholar 

  49. Buiting, K. et al. Expressed copies of the MN7 (D15F37) gene family map close to the common deletion breakpoints in the Prader–Willi/Angelman syndromes. Cytogenet. Cell Genet. 81, 247–253 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Ji, Y. et al. The ancestral gene for transcribed, low-copy repeats in the Prader–Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities. Hum. Mol. Genet. 8, 533–542 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Carrozzo, R. et al. Inter- and intrachromosomal rearrangements are both involved in the origin of 15q11–q13 deletions in Prader–Willi syndrome. Am. J. Hum. Genet. 61, 228–231 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Robinson, W. P. et al. The mechanisms involved in formation of deletions and duplications of 15q11–q13. J. Med. Genet. 35, 130–136 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Horsthemke, B. et al. Familial translocations involving 15q11–q13 can give rise to interstitial deletions causing Prader–Willi or Angelman syndrome. J. Med. Genet. 33, 848–851 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Robinson, W. P. et al. Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15. Clin. Genet. 57, 349–358 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Buiting, K. et al. Epimutations in Prader–Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am. J. Hum. Genet. 72, 571–577 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Buiting, K., Lich, C., Cottrell, S., Barnicoat, A. & Horsthemke, B. A. 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum. Genet. 105, 665–666 (1999).

    CAS  PubMed  Google Scholar 

  57. Lewis, M. W. et al. Angelman syndrome imprinting center encodes a transcriptional promoter. Proc. Natl Acad. Sci. USA 112, 6871–6875 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Buiting, K. et al. Sporadic imprinting defects in Prader–Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am. J. Hum. Genet. 63, 170–180 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Buiting, K. Prader–Willi syndrome and Angelman syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 154C, 365–376 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Nazlican, H. et al. Somatic mosaicism in patients with Angelman syndrome and an imprinting defect. Hum. Mol. Genet. 13, 2547–2555 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Malzac, P. et al. Mutation analysis of UBE3A in Angelman syndrome patients. Am. J. Hum. Genet. 62, 1353–1360 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Russo, S. et al. Novel mutations of ubiquitin protein ligase 3A gene in Italian patients with Angelman syndrome. Hum. Mutat. 15, 387 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Lossie, A. C. et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 38, 834–845 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Camprubí, C. et al. Novel UBE3A mutations causing Angelman syndrome: different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions. Am. J. Med. Genet. A 149A, 343–348 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Sadikovic, B. et al. Mutation update for UBE3A variants in Angelman syndrome. Hum. Mutat. 35, 1407–1417 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Hosoki, K., Takano, K., Sudo, A., Tanaka, S. & Saitoh, S. Germline mosaicism of a novel UBE3A mutation in Angelman syndrome. Am. J. Med. Genet. A 138A, 187–189 (2005).

    Article  PubMed  Google Scholar 

  67. Sugimoto, T. et al. Angelman syndrome in three siblings: characteristic epileptic seizures and EEG abnormalities. Epilepsia 33, 1078–1082 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Burger, J., Horn, D., Tonnies, H., Neitzel, H. & Reis, A. Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader–Willi syndrome. Am. J. Med. Genet. 111, 233–237 (2002).

    Article  PubMed  Google Scholar 

  69. Boyes, L. et al. Detection of a deletion of exons 8–16 of the UBE3A gene in familial Angelman syndrome using a semi-quantitative dosage PCR based assay. Eur. J. Med. Genet. 49, 472–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Sato, K. et al. Angelman syndrome caused by an identical familial 1,487-kb deletion. Am. J. Med. Genet. A 143A, 98–101 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Kuroda, Y. et al. Deletion of UBE3A in brothers with Angelman syndrome at the breakpoint with an inversion at 15q11.2. Am. J. Med. Genet. A 164A, 2873–2878 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Reiter, L. T., Seagroves, T. N., Bowers, M. & Bier, E. Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. Hum. Mol. Genet. 15, 2825–2835 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Huibregtse, J. M., Scheffner, M. & Howley, P. M. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 10, 4129–4135 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mishra, A., Godavarthi, S. K. & Jana, N. R. UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol. Dis. 36, 26–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Kumar, S., Talis, A. L. & Howley, P. M. Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J. Biol. Chem. 274, 18785–18792 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Margolis, S. S. et al. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 143, 442–455 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kuhnle, S., Mothes, B., Matentzoglu, K. & Scheffner, M. Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc. Natl Acad. Sci. USA 110, 8888–8893 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Uhlén, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Bruinsma, C. F. et al. Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model. J. Clin. Invest. 125, 4305–4315 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Moncla, A. et al. Phenotype–genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur. J. Hum. Genet. 7, 131–139 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Gentile, J. K. et al. A neurodevelopmental survey of Angelman syndrome with genotype–phenotype correlations. J. Dev. Behav. Pediatr. 31, 592–601 (2010).

    PubMed  PubMed Central  Google Scholar 

  83. Low, D. & Chen, K. S. UBE3A regulates MC1R expression: a link to hypopigmentation in Angelman syndrome. Pigment Cell Melanoma Res. 24, 944–952 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Sahoo, T. et al. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype–phenotype correlations. J. Med. Genet. 43, 512–516 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Valente, K. D. et al. Angelman syndrome caused by deletion: a genotype–phenotype correlation determined by breakpoint. Epilepsy Res. 105, 234–239 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Brennan, M. L. et al. Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects. Am. J. Med. Genet. A 167A, 142–146 (2015).

    Article  PubMed  Google Scholar 

  87. Fairbrother, L. C. et al. Mild Angelman syndrome phenotype due to a mosaic methylation imprinting defect. Am. J. Med. Genet. A 167A, 1565–1569 (2015).

    Article  CAS  Google Scholar 

  88. Tan, W. H., Bird, L. M., Thibert, R. L. & Williams, C. A. If not Angelman, what is it? A review of Angelman-like syndromes. Am. J. Med. Genet. A 164A, 975–992 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Williams, C. A., Lossie, A. & Driscoll, D. Angelman syndrome: mimicking conditions and phenotypes. Am. J. Med. Genet. 101, 59–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Tan, W. H. & Bird, L. M. Pharmacological therapies for Angelman syndrome. Wien. Med. Wochenschr. http://dx.doi.org/10.1007/s10354-015-0408-z (2016).

  91. Thibert, R. L., Larson, A. M., Hsieh, D. T., Raby, A. R. & Thiele, E. A. Neurologic manifestations of Angelman syndrome. Pediatr. Neurol. 48, 271–279 (2013).

    Article  PubMed  Google Scholar 

  92. Thibert, R. L. et al. Low glycemic index treatment for seizures in Angelman syndrome. Epilepsia 53, 1498–1502 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Evangeliou, A. et al. Ketogenic diet in a patient with Angelman syndrome. Pediatr. Int. 52, 831–834 (2010).

    Article  PubMed  Google Scholar 

  94. Sewell, M. D. et al. A retrospective review to assess whether spinal fusion and scoliosis correction improved activity and participation for children with Angelman syndrome: brief report. Dev. Neurorehabil. 19, 315–320 (2016).

    PubMed  Google Scholar 

  95. Strachan, R. et al. Experimental functional analysis of aggression in children with Angelman syndrome. Res. Dev. Disabil. 30, 1095–1106 (2009).

    Article  PubMed  Google Scholar 

  96. Bruni, O. et al. Sleep disturbances in Angelman syndrome: a questionnaire study. Brain Dev. 26, 233–240 (2004).

    Article  PubMed  Google Scholar 

  97. Conant, K. D., Thibert, R. L. & Thiele, E. A. Epilepsy and the sleep–wake patterns found in Angelman syndrome. Epilepsia 50, 2497–2500 (2009).

    Article  PubMed  Google Scholar 

  98. Didden, R., Korzilius, H., Smits, M. G. & Curfs, L. M. Sleep problems in individuals with Angelman syndrome. Am. J. Ment. Retard. 109, 275–284 (2004).

    Article  PubMed  Google Scholar 

  99. Goldman, S. E., Bichell, T. J., Surdyka, K. & Malow, B. A. Sleep in children and adolescents with Angelman syndrome: association with parent sleep and stress. J. Intellect. Disabil. Res. 56, 600–608 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Walz, N. C., Beebe, D. & Byars, K. Sleep in individuals with Angelman syndrome: parent perceptions of patterns and problems. Am. J. Ment. Retard. 110, 243–252 (2005).

    Article  PubMed  Google Scholar 

  101. Braam, W., Didden, R., Smits, M. G. & Curfs, L. M. Melatonin for chronic insomnia in Angelman syndrome: a randomized placebo-controlled trial. J. Child Neurol. 23, 649–654 (2008).

    Article  PubMed  Google Scholar 

  102. Takaesu, Y., Komada, Y. & Inoue, Y. Melatonin profile and its relation to circadian rhythm sleep disorders in Angelman syndrome patients. Sleep Med. 13, 1164–1170 (2012).

    Article  PubMed  Google Scholar 

  103. Zhdanova, I. V., Wurtman, R. J. & Wagstaff, J. Effects of a low dose of melatonin on sleep in children with Angelman syndrome. J. Pediatr. Endocrinol. Metab. 12, 57–67 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Allen, K. D., Kuhn, B. R., DeHaai, K. A. & Wallace, D. P. Evaluation of a behavioral treatment package to reduce sleep problems in children with Angelman syndrome. Res. Dev. Disabil. 34, 676–686 (2013).

    Article  PubMed  Google Scholar 

  105. Summers, J. A. et al. A combined behavioral/pharmacological treatment of sleep–wake schedule disorder in Angelman syndrome. J. Dev. Behav. Pediatr. 13, 284–287 (1992).

    Article  CAS  PubMed  Google Scholar 

  106. Bird, L. M. et al. A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome. Am. J. Med. Genet. A 155A, 2956–2963 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Huang, H. S. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481, 185–189 (2012).

    Article  CAS  Google Scholar 

  108. King, I. F. et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Meng, L. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518, 409–412 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Silva-Santos, S. et al. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J. Clin. Invest. 125, 2069–2076 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Jasmin Beygo and Deniz Kanber for critical reading of the manuscript. Part of this work was funded by the Bundesministerium für Bildung und Forschung (BMBF; Imprinting diseases, grant No. 01GM1513A).

Author information

Authors and Affiliations

  1. Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, Essen, D-45122, Germany

    Karin Buiting & Bernhard Horsthemke

  2. Division of Genetics and Metabolism, Department of Pediatrics, Raymond C. Philips Unit, University of Florida, 1600 SW Archer Road, PO Box 100296, Gainesville, 32610–0296, Florida, USA

    Charles Williams

Authors
  1. Karin Buiting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bernhard Horsthemke
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to all aspects of the manuscript.

Corresponding author

Correspondence to Karin Buiting.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Uniparental disomy

A situation in which both copies of a chromosome are inherited from the same parent, rather than one being inherited from the mother and the other from the father.

Genomic imprinting

An epigenetic process that leads to monoallelic gene expression in a parent-of-origin-specific manner. At imprinted loci, one parental gene copy is expressed while the other is silenced, leading to the existence of genes that are expressed from the paternal or maternal allele only.

Non-homologous recombination

A recombination event that occurs between two chromosome regions with high but not identical DNA sequence similarity. Fusions among identical chromosome regions are termed homologous recombinations.

Breakpoint cluster regions

Locations in the human genome where recurrent disruptions or breaks occur.

Low copy repeats

Highly similar sequence elements within the human genome. They are typically 50–500 kb in length with >95% sequence identity. Low copy repeats are associated with regions of non-homologous recombination.

Maternal nondisjunction

An event that occurs when chromosome pairs fail to separate during the first meiotic division, or when the two chromatids of a chromosome fail to separate during the second meiotic division, or during mitosis. Nondisjunction results in cells with abnormal chromosome numbers.

Robertsonian translocation

Robertsonian translocations are chromosomal rearrangements that result from the fusion of the entire long arms of two acrocentric chromosomes. The five human acrocentric chromosome pairs are chromosomes 13, 14, 15, 21 and 22.

Marker chromosome

A structurally abnormal chromosome fragment that cannot be unambiguously identified by conventional cytogenetics. The risk of phenotypic abnormalities associated with a marker chromosome depends on what genetic material is contained within the marker.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buiting, K., Williams, C. & Horsthemke, B. Angelman syndrome — insights into a rare neurogenetic disorder. Nat Rev Neurol 12, 584–593 (2016). https://doi.org/10.1038/nrneurol.2016.133

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2016.133

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing