Epilepsy and EEG features in Angelman syndrome

Angelman syndrome (AS) is an orphan disease caused by loss of function of the maternal allele of the UBE3A gene on chromosome 15 (region 15q11.2-q13), characterized by severe mental and speech retardation, movement disorders, unique behavior in the form of frequent laughter, and epileptic seizures with characteristic anomalies in  EEG. Epilepsy is often drug-resistant, generalized seizure types dominate, among which myoclonic seizures and atypical absences are the most common. Infantile spasms are rare in AS children, but the EEG pattern, especially in infancy, in the form of diffuse slow-wave activity with multiregional and generalized epileptiform activity, may resemble a hypsarrhythmia pattern. We present own observation of a child in whom the EEG was incorrectly described as a hypsarrhythmia pattern, and hormonal therapy was prescribed with suspicion of epileptic spasms. In this article, we made a brief review of the literature on the treatment of epilepsy in AS patients with a recommended algorithm for choosing an antiepileptic drug (AED). In young children with developmental delay, a routine EEG pattern similar to hypsarrhythmia, but with out of clinical and EEG patterns of spasms, it is necessary to conduct video-EEG monitoring with recording of sleep, to exclude the “pseudo-hypsarrhythmia” pattern, which is especially important when Angelman syndrome is suspected. In the treatment of epilepsy in Angelman syndrome, it is necessary to adhere to the recommended, according to the literature, algorithm for choosing AEDs.

Compliance with ethical standards. Informed voluntary consent was obtained from the patient’s parents.

Contribution:
Gorchkhanova Z.K. — concept, writing text;
Belousova E.D. — concept, writing text;
Nikolaeva E.A. — concept, editing;
Pivovarova A.M. — editing.
All co-authors — responsibility for the integrity of all parts of the manuscript and approval of its final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgement. The study had no sponsorship.

Received: June 21, 2023
Accepted:  August 30, 2023
Published: October 13, 2023

1. Debopam S. Epilepsy in Angelman syndrome: A scoping review. Brain Dev. 2020; 43(1): 32–44. https://doi.org/10.1016/j.braindev.2020.08.014

2. Carson R.P., Bird L., Childers A.K., Wheeler F., Duis J. Preserved expressive language as a phenotypic determinant of Mosaic Angelman Syndrome. Mol. Genet. Genomic Med. 2019; 7(9): e837. https://doi.org/10.1002/mgg3.837

3. Aypar U., Hoppman N.L., Thorland E.C., Dawson D.B. Patients with mosaic methylation patterns of the Prader-Willi/Angelman Syndrome critical region exhibit AS-like phenotypes with some PWS features. Mol. Cytogenet. 2016; 9: 26. https://doi.org/10.1186/s13039-016-0233-0

4. Fairbrother L.C., Cytrynbaum C., Boutis P., Buiting K., Weksberg R., Williams C. Mild Angelman syndrome phenotype due to a mosaic methylation imprinting defect. Am. J. Med. Genet. A. 2015; 167(7): 1565–9. https://doi.org/10.1002/ajmg.a.37058

5. Bindels-de Heus K., Mous S.E., Ten Hooven-Radstaake M., van Iperen-Kolk B.M., Navis C., Rietman A.B., et al. An overview of health issues and development in a large clinical cohort of children with Angelman syndrome. Am. J. Med. Genet. A. 2020; 182(1): 53–63. https://doi.org/10.1002/ajmg.a.61382

6. Sahoo T., Bacino C.A., German J.R., Shaw C.A., Bird L.M., Kimonis V., et al. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations. Eur. J. Hum. Genet. 2007; 15(9): 943–9. https://doi.org/10.1038/sj.ejhg.5201859

7. Han J., Bichell T.J., Golden S., Anselm I., Waisbren S., Bacino C.A., et al. A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome. Orphanet J. Rare Dis. 2019; 14(1): 232. https://doi.org/10.1186/s13023-019-1216-0

8. Pelc K., Boyd S.G., Cheron G., Dan B. Epilepsy in Angelman syndrome. Seizure. 2008; 17(3): 211–7. https://doi.org/10.1016/j.seizure.2007.08.004

9. Williams C.A., Beaudet A.L., Clayton-Smith J., Knoll J.H., Kyllerman M., Laan L.A., et al. Angelman syndrome 2005: Updated consensus for diagnostic criteria. Am. J. Med. Genet. A. 2006; 140(5): 413–8. https://doi.org/10.1002/ajmg.a.31074

10. Moncla A., Malzac P., Voelckel M., Auquier P., Girardot L., Mattei M., et al. Phenotype–genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur. J. Hum. Genet. 1999; 7(2): 131–9. https://doi.org/10.1038/sj.ejhg.5200258

11. Khan N., Cabo R., Tan W.H., Tayag R., Bird L.M. Healthcare burden among individuals with Angelman syndrome: Findings from the Angelman Syndrome Natural History Study. Mol. Genet. Genomic Med. 2019; 7(7): e00734. https://doi.org/10.1002/mgg3.734

12. Thibert R.L., Larson A.M., Hsieh D.T., Raby A.R., Thiele E.A. Neurologic manifestations of Angelman syndrome. Pediatr. Neurol. 2013; 48(4): 271–9. https://doi.org/10.1016/j.pediatrneurol.2012.09.015

13. Prasad A., Grocott O., Parkin K., Larson A., Thibert R.L. Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases. Am. J. Med. Genet. A. 2018; 176(6): 1327–34. https://doi.org/10.1002/ajmg.a.38694

14. Bakke K.A., Howlin P., Retterstøl L., Kanavin Ø.J., Heiberg A., Nærland T. Effect of epilepsy on autism symptoms in Angelman syndrome. Mol. Autism. 2018; 9: 2. https://doi.org/10.1186/s13229-017-0185-1

15. Gorchkhanova Z.K., Nikolaeva E.A., Bochenkov S.V., Belousova E.D. Clinical manifestations of Angelman syndrome in children. Rossiyskiy vestnik perinatologii i pediatrii. 2021; 66(6): 63–70. https://doi.org/10.21508/1027-4065-2021-66-6-63-70 https://elibrary.ru/hywuxb (in Russian)

16. Fujikawa Y., Sugai K., Hanaoka S., Fukumizu M., Sasaki M., Kaga M. Three cases with severe motor and intellectual disabilities presenting the severest condition caused by prolonged non-convulsive status epilepticus. No To Hattatsu. 2003; 35(1): 43–8. (in Japanese)

17. Ohtsuka Y., Kobayashi K., Yoshinaga H., Ogino T., Ohmori I., Ogawa K., et al. Relationship between severity of epilepsy and developmental outcome in Angelman syndrome. Brain Dev. 2005; 27(2): 95–100. https://doi.org/10.1016/j.braindev.2003.09.015

18. Yang X.Y., Zou L.P., Song F., Zhang L.P., Zheng H., Wu H.S., et al. Clinical manifestation and EEG characteristics of Angelman syndrome. Zhonghua Er Ke Za Zhi. 2010; 48(10): 783–6. (in Chinese)

19. Pollack S.F., Grocott O.R., Parkin K.A., Larson A.M., Thibert R.L. Myoclonus in Angelman syndrome. Epilepsy Behav. 2018; 82: 170–4. https://doi.org/10.1016/j.yebeh.2018.02.006

20. Casara G.L., Vecchi M., Boniver C., Drigo P., Baccichetti C., Artifoni L., et al. Electroclinical diagnosis of Angelman syndrome: a study of 7 cases. Brain Dev. 1995; 17(1): 64–8. https://doi.org/10.1016/0387-7604(94)00104-6

21. Korff C.M., Kelley K.R., Nordli D.R. Jr. Notched delta, phenotype, and Angelman syndrome. J. Clin. Neurophysiol. 2005; 22(4): 238–43. https://doi.org/10.1097/01.wnp.0000167930.90824.0f

22. Sidorov M.S., Deck G.M., Dolatshahi M., Thibert R.L., Bird L.M., Chu C.J., et al. Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis. J. Neurodev. Disord. 2017; 9: 17. https://doi.org/10.1186/s11689-017-9195-8

23. Vendrame M., Loddenkemper T., Zarowski M., Gregas M., Shuhaiber H., Sarco D.P., et al. Analysis of EEG patterns and genotypes in patients with Angelman syndrome. Epilepsy Behav. 2012; 23(3): 261–5. https://doi.org/10.1016/j.yebeh.2011.11.027

24. Darteyre S., Mazzola L., Convers P., Lebrun M., Ville D. Angelman syndrome and pseudo-hypsarrhythmia: a diagnostic pitfall. Epileptic Disord. 2011; 13(3): 331–5. https://doi.org/10.1684/epd.2011.0446

25. Gorchkhanova Z.K., Nikolaeva E.A., Pivovarova A.M., Bochenkov S.V., Belousova E.D. Difficulties in the differential diagnosis of Angelman’s syndrome. Rossiyskiy vestnik perinatologii i pediatrii. 2022; 67(6): 113–22. https://doi.org/10.21508/1027-4065-2022-67-6-113-122 https://elibrary.ru/jzquzk (in Russian)

26. Laan L.A., Vein A.A. A Rett patient with a typical Angelman EEG. Epilepsia. 2002; 43(12): 1590–2. https://doi.org/10.1046/j.1528-1157.2002.30802.x

27. Sgrò V., Riva E., Canevini M.P., Colamaria V., Rottoli A., Minotti L., et al. 4p(-) syndrome: a chromosomal disorder associated with a particular EEG pattern. Epilepsia. 1995; 36(12): 1206–14. https://doi.org/10.1111/j.1528-1157.1995.tb01064.x

28. Valente K.D., Andrade J.Q., Grossmann R.M., Kok F., Fridman C., Koiffmann C.P., et al. Angelman syndrome: Difficulties in EEG pattern recognition and possible misinterpretations. Epilepsia. 2003; 44(8): 1051–63. https://doi.org/10.1046/j.1528-1157.2003.66502.x

29. Dan B., Boyd S.G., Pelc K., Cheron G. Lamotrigine effect on GABA transmission in Angelman syndrome? Epilepsia. 2007; 48(8): 1634. https://doi.org/10.1111/j.1528-1167.2007.01178_5.x

30. Ostergaard J.R., Balslev T. Efficacy of different antiepileptic drugs in children with Angelman syndrome associated with 15q11-13 deletion: the Danish experience. Dev. Med. Child Neurol. 2001; 43(10): 718–9. https://doi.org/10.1017/s0012162201001293

31. Shaaya E.A., Grocott O.R., Laing O., Thibert R.L. Seizure treatment in Angelman syndrome: a case series from the Angelman syndrome clinic at Massachusetts General Hospital. Epilepsy Behav. 2016; 60: 138–41. https://doi.org/10.1016/j.yebeh.2016.04.030

32. Evangeliou A., Doulioglou V., Haidopoulou K., Aptouramani M., Spilioti M., Varlamis G. Ketogenic diet in a patient with Angelman syndrome. Pediatr. Int. 2010; 52(5): 831–4. https://doi.org/10.1111/j.1442-200X.2010.03118.x

33. Groesbeck D.K., Bluml R.M., Kossoff E.H. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev. Med. Child Neurol. 2006; 48(12): 978–81. https://doi.org/10.1017/s0012162206002143

34. Grocott O.R., Herrington K.S., Pfeifer H.H., Thiele E.A., Thibert R.L. Low glycemic index treatment for seizure control in Angelman syndrome: A case series from the Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital. Epilepsy Behav. 2017; 68: 45–50. https://doi.org/10.1016/j.yebeh.2016.12.018

35. Thibert R.L., Pfeifer H.H., Larson A.M., Raby A.R., Reynolds A.A., Morgan A.K., et al. Low glycemic index treatment for seizures in Angelman syndrome. Epilepsia. 2012; 53(9): 1498–502. https://doi.org/10.1111/j.1528-1167.2012.03537.x

36. Dion M.H., Novotny E.J. Jr., Carmant L., Cossette P., Nguyen D.K. Lamotrigine therapy of epilepsy with Angelman’s syndrome. Epilepsy. 2007; 48(3): 593–6. https://doi.org/10.1111/j.1528-1167.2006.00969.x

37. Thibert R.L., Conant K.D., Braun E.K., Bruno P., Said R.R., Nespeca M.P., et al. Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia. 2009; 50(11): 2369–76. https://doi.org/10.1111/j.1528-1167.2009.02108.x

38. Sugiura C., Ogura K., Ueno M., Toyoshima M., Oka A. High-dose ethosuximide for epilepsy in Angelman syndrome: implication of GABA(A) receptor subunit. Neurology. 2001; 57(8): 1518–9. https://doi.org/10.1212/wnl.57.8.1518

39. Bobylova M.Yu., Mukhin K.Yu., Kuzmich G.V., Glukhova L.Yu., Pylayeva O.A. Epilepsy in Angelman syndrome. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2022; 122(7): 100–5. https://doi.org/10.17116/jnevro2022122071100 https://elibrary.ru/akndjx (in Russian)

40. Kawano O., Egawa K., Shiraishi H. Perampanel for nonepileptic myoclonus in Angelman syndrome. Brain Dev. 2020; 42(5): 389–92. https://doi.org/10.1016/j.braindev.2020.02.007

41. Tomei K.L., Mau C.Y., Ghali M., Pak J., Goldstein I.M. Vagal nerve stimulation for medically refractory epilepsy in Angelman syndrome: a series of three cases. Childs Nerv. Syst. 2018; 34(3): 395–400. https://doi.org/10.1007/s00381-018-3723-z

42. Forrest K.M., Young H., Dale R.C., Gill D.S. Benefit of corticosteroid therapy in Angelman syndrome. J. Child Neurol. 2009; 24(8): 952–8. https://doi.org/10.1177/0883073808331344

43. Nolt D.H., Mott J.M., Lopez W.L. Assessment of anticonvulsant effectiveness and safety in patients with Angelman’s syndrome using an Internet questionnaire. Am. J. Health Syst. Pharm. 2003; 60(24): 2583–7. https://doi.org/10.1093/ajhp/60.24.2583

44. Samanta D. Cannabidiol: A review of clinical efficacy and safety in epilepsy. Pediatr. Neurol. 2019; 96: 24–9. https://doi.org/10.1016/j.pediatrneurol.2019.03.014

45. Samanta D. Changing landscape of Dravet syndrome management: an overview. Neuropediatrics. 2020; 51(2): 135–45. https://doi.org/10.1055/s-0040-1701694

46. Worden L., Grocott O., Tourjee A., Chan F., Thibert R. Diazepam for outpatient treatment of nonconvulsive status epilepticus in pediatric patients with Angelman syndrome. Epilepsy Behav. 2018; 82: 74–80. https://doi.org/10.1016/j.yebeh.2018.02.027

47. Duis J., Nespeca M., Summers J., Bird L., Bindels-de Heus K.G.C.B., Valstar M.J., et al. A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome. Mol. Genet. Genomic Med. 2022; 10(3): e1843. https://doi.org/10.1002/mgg3.1843