Angelman Syndrome Reviewed from a Neurophysiological Perspective. The UBE3A-GABRB3 Hypothesis

Abstract

Angelman syndrome is characterised by neurodevelopmental impairment (with or without epileptic seizures) associated with functional deficit of the UBE3A gene. Different mechanisms of UBE3A inactivation correlate with clinical phenotypes of varying severity. However, three distinctive, highly consistent electroencephalographic rhythmic patterns can be observed in almost all patients irrespective of genotype, clinical severity and the presence or severity of a seizure disorder. Pattern I consists of runs of high amplitude 2 - 3/s rhythmic activity predominating over the frontal regions. Pattern II consists of more diffuse runs of 4 - 6/s rhythmic activity. Pattern III consists of bursts or runs of high amplitude 3 - 5/s rhythmic activity, maximal over the occipital region, sometimes containing small spikes and facilitated by eye closure. We review the available neurophysiological evidence from human and animal studies in the light of recent molecular advances. Electroencephalographic features in both patients and various mouse models point to two separable categories: characteristic rhythmic patterns, which are not related to epilepsy, and less specific epilepsy-related discharge activity. These features are consistent with a model of cortical and thalamo-cortical dysfunction resulting from dysregulation of synaptic GABAergic neurotransmission by (1) deficient recruitment of functional GABA_A receptors related to reduced UBE3A gene expression in all cases and (2) decreased amount of β3 sub-unit in these receptors related to reduced GABRB3 gene expression in deletion cases.

Key words

Angelman syndrome - EEG - UBE3A - GABA_A - epilepsy - chromosome 15

References

• 1 Aguglia U, Le Piane E, Gambardella A, Messina D, Russo C, Sirchia S M, Porta G, Quattrone A. Emotion-induced myoclonic absence-like seizures in a patient with inv-dup (15) syndrome: a clinical, EEG, and molecular genetic study.  Epilepsia. 1999;  40 1316-1319
• 2 Albrecht U, Sutcliffe J S, Cattanach B M, Beechey C V, Armstrong D, Eichele G, Beaudet A L. Imprinted expression of the murine Angelman syndrome gene Ube3a, in hippocampal and Purkinje neurons.  Nat Genet. 1997;  17 75-78
• 3 Angelman H. “Puppet” Children: a report on three cases.  Dev Med Child Neurol. 1965;  7 681-688
• 4 Battaglia A, Gurrieri F, Bertini E, Bellacosa A, Pomponi M G, Paravatou-Pertsotas M, Mazza S, Neri G. The inv dup(15) syndrome: a clinically recognisable syndrome with altered behaviour, mental retardation and epilepsy.  Neurology. 1997;  48 1081-1086
• 5 Bedford F K, Kittler J T, Muller E, Thomas P, Uren G M, Merlo D, Wisdon W, Triller A, Smart T G, Moss S J. GABA_A receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1.  Nat Neurosci. 2001;  4 908-916
• 6 Bianchi M T, Song L, Zhang H, Macdonald R L. Two different mechanisms of disinhibition produced by GABA-A receptor mutations linked to epilepsy in humans.  J Neurosci. 2002;  22 5321-5327
• 7 Blumenfeld H, McCormick D A. Corticothalamic inputs control the pattern of activity generated in thalamocortical networks.  J Neurosci. 2000;  20 5153-5162
• 8 Boyd S G, Cross J H, Dan B. EEG features in Angelman syndrome.  Eur J Paediatr Neurol. 1997;  1 A1-A2
• 9 Boyd S G, Dan B. Cerebral dysplasias: reviewed from a neurophysiological perspective.  Neuropediatrics. 2001;  32 279-285
• 10 Boyd S G, Harden A, Patton M A. The EEG in early diagnosis of the Angelman (happy puppet) syndrome.  Eur J Pediatr. 1988;  147 508-513
• 11 Bower B D, Jeavons P M. The “Happy Puppet” syndrome.  Arch Dis Child. 1967;  42 298-302
• 12 Brockmann K, Böhm R, Bürger J. Exceptionally mild Angelman syndrome phenotype associated with an incomplete imprinting defect.  J Med Genet. 2002;  39 e51
• 13 Browne S H, Kang J, Akk G, Chiang L W, Schulman H, Hugenard J R, Prince D A. Kinetic and pharmacological properties of GABA(A) receptors in single thalamic neurons and GABA(A) subunit expression.  J Neurophysiol. 2001;  86 2312-2322
• 14 Buoni S, Grosso S, Pucci L, Fois A. Diagnosis of Angelman syndrome: clinical and EEG criteria.  Brain Dev. 1999;  21 296-302
• 15 Burbea M, Drier L, Dittman J S, Grunwald M E, Kaplan J M. Ubiquitin and AP180 regulate the abundance of GLR-1 Glutamate receptors at postsynaptic elements in C. elegans.  Neuron. 2002;  33 107-120
• 16 Bürger J, Kunze J, Sperling K, Reis A. Phenotypic differences in Angelman syndrome patients: imprinting mutations show less frequently microcephaly and hypopigmentation than deletions.  Am J Med Genet. 1996;  66 221-226
• 17 Casara G L, Vecchi M, Boniver C, Drigo P, Baccichetti C, Artifoni L, Franzoni E, Marchiani V. Electroclinical diagnosis of Angelman syndrome: a study of 7 cases.  Brain Dev. 1995;  17 64-68
• 18 Cattanach B M, Barr J A, Beechey C V, Martin J, Noebels J, Jones J. A candidate model for Angelman syndrome in the mouse.  Mamm Genome. 1997;  8 472-478
• 19 Chugani D C, Muzik O, Juhasz C, Janisse J J, Ager J, Chugani H T. Postnatal maturation of human GABA receptors measured with positron emission tomography.  Ann Neurol. 2001;  49 618-626
• 20 Clayton-Smith J. Clinical Research on Angelman syndrome in the United kingdom: observations on 82 affected individuals.  Am J Med Genet. 1993;  46 12-15
• 21 Clayton-Smith J, Laan Angelman syndrome L. a review of the clinical and genetic aspects.  J Med Genet. 2003;  40 87-95
• 22 Cobb W A, Gordon N, Matthews C, Nieman E A. The occipital delta rhythms in petit mal. Electroencephalogr.  Clin Neurophysiol. 1961;  13 142-143
• 23 Cook Jr E H, Lindgren V, Leventhal B L, Courchesne R, Linken A, Shulman C, Lord C, Courchesne E. Autism or atypical autism in maternally but not paternally derived proximal 15 q duplication.  Am J Hum Genet. 1997;  60 928-934
• 24 Dalla Bernardina B, Fontana E, Zullini E, La Selva L, Franco A, Darra F, Piardi F, Avesani E. Angelman syndrome: electroclinical features of 10 personal cases.  Gaslini. 1995;  27 (Suppl 1) 75-78
• 25 Dan B, Boyd S G, Christiaens F, Courtens W, Van Maldergem L, Vamos E, Kahn A. Atypical forms of Angelman syndrome.  Eur J Paediatr Neurol. 1997;  1 A4-A5
• 26 Dan B, Boyd S G, Christiaens F, Courtens W, Van Maldergem L, Kahn A. Atypical features in Angelman syndrome due to imprinting defect or uniparental disomy of chromosome 15.  Neuropediatrics. 2000;  31 109-110
• 27 Dan B, Cheron G. Le syndrome d'Angelman: un modèle clinique et génétique.  Rev Neurol (Paris). 2003;  5 499-510
• 28 DeLorey T M, Handforth A, Anagnostaras S G, Homanics G E, Minassian B A, Asatourian A, Fanselow M S, Delgado-Escueta A, Ellison G D, Olsen R W. Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.  J Neurosci. 1998;  18 8505-8514
• 29 Döose H, Baier W K. Theta rhythms in the EEG: a genetic trait in childhood epilepsy.  Brain Dev. 1988;  10 347-354
• 30 Dörries A, Spohr H L, Kunze J. Angelman (“happy puppet”) syndrome - seven new cases documented by cerebral computed tomography: review of the literature.  Eur J Pediatr. 1988;  148 270-273
• 31 Ebert M H, Schmidt D E, Thompson T, Buttler M G. Elevated plasma gamma-aminobutyric acid (GABA) levels in individuals with either Prader-Willi syndrome or Angelman syndrome. J Neuropsychiatry Clin Neuropsy.  . 1997;  9 75-80
• 32 Elia Guerrini M R, Musumeci S A, Bonanni P, Gambardella A, Aguglia U. Myoclonic-absence-like seizures and chromosome abnormality syndromes.  Epilepsia. 1998;  39 660-663
• 33 Feucht M, Fuchs K, Pichlbauer E, Hornik K, Scharfetter J, Goessler R, Füreder T, Cvetkovic N, Sieghart W, Kasper S, Aschauer H. Possible association between childhood absence epilepsy and the gene encoding GABRB3.  Biol Psychiatry. 1999;  46 997-1002
• 34 Gabriel J M, Merchant M, Ohta T, Ji Y, Caldwell R G, Ramsey M J, Tiucker J D, Longnecker R, Nicholls R D. A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and Angelman syndromes.  Proc Natl Acad Sci. 1999;  96 9258-9263
• 35 Ganji S, Duncan M C. Angelman's (happy puppet) syndrome: clinical, CT scan and serial electroencephalographic study.  Clin Electroencephalogr. 1989;  20 128-140
• 36 Gastaut H, Pinsard N, Raybaud C L, Aicardi J, Zifkin B. Lissencephaly agyria-pachygyria): clinical findings and serial EEG studies.  Dev Med Child Neurol. 1987;  29 167-180
• 37 Gibbs JW 3rd . Anticonvulsant actions of lamotrigine on spontaneous thalamocortical rhythms.  Epilepsia. 2002;  43 342-349
• 38 Gillberg C, Steffenburg S, Wahlström J, Gillberg I C, Sjöstedt A, Martensson Liedgren T S, Eeg-Olofsson O. Autism associated with marker chromosome.  J Am Acad Child Adolesc Psychiatry. 1991;  30 489-494
• 39 Gillessen-Kaesbach G, Demuth S, Thiele H, Theile U, Lich C, Horsthemke B. A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect.  Eur J Hum Genet. 1999;  7 638-644
• 40 Grosse P, Guerrini R, Parmeggiani L, Bonanni P, Pogosyan A, Brown P. Abnormal corticomuscular and intermuscular coupling in high-frequency rhythmic myoclonus.  Brain. 2003;  126 326-342
• 41 Guerrini R, De Lorey T M, Bonanni P, Moncla A, Dravet C, Suisse G, Livet M O, Bureau M, Malzac P, Genton P, Thomas P, Santucci F, Simi P, Serratosa J M. Cortical myoclonus in Angelman syndrome.  Ann Neurol. 1996;  40 39-48
• 42 Herzing J B, Kim S J, Cook Jr E H, Ledbetter D H. The human aminophospholipid-transporting ATPase gene ATP10 C maps adjacent to UBE3A and exhibits similar imprinted expression.  Am J Hum Genet. 2001;  68 1501-150
• 43 Holopainen I E, Metsahonkala E L, Kokkonen H, Parkkola R K, Manner T E, Nagren K, Korpi E R. Decreased binding of [¹¹C]flumazenil in Angelman syndrome patients with GABA(A) receptor beta3 subunit deletions.  Ann Neurol. 2001;  49 110-113
• 44 Homanics G E, DeLorey T M, Firestone L L, Quinlan J J, Handforth A, Harrison N L, Krasowski M D, Rick C EM, Korpi E M, Makela R, Brilliant M, Hagiwara N, Ferguson C, Snyder K, Olsen R W. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.  Proc Natl Acad Sci. 1997;  94 4143-4148
• 45 Hosford D A, Lin F H, Wang Y, Caddick S J. Studies of the lethargic (lh/lh) mouse model of absence seizures: Regulatory mechanisms and identification of the lh gene. Part One: GABA receptors in the lh/lh mouse model of absence seizures. Delgado-Escueta AV, Wilson WA, Olsen RW, Porter RJ Jasper's Basic Mechanisms of the Epilepsies. 3rd ed. Adv. Neurol. 79. Philadelphia; Lippincott Williams and Wilkins 1999: 240-247
• 46 Huntsman M M, Porcello D M, Hoomanics G E, DeLorey T M, Huguenard J R. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus.  Science. 1999;  283 541-543
• 47 Jay V, Becker L E, Chan F W, Perry Sr T L. Puppet-like syndrome of Angelman: a pathological and neurochemical study.  Neurology. 1991;  41 416-422
• 48 Jiang Y, Armstrong D, Albrecht U, Atkins C M, Noebels J L, Eichele G, Sweatt J D, Beaudet A L. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and lkong-term potentiation.  Neuron. 1998;  21 799-811
• 49 Kandel A, Buzsaki G. Cellular-synaptic generation of sleep spindles, spike-and-wave discharges and evoked thalamocortical responses in the neocortex of the rat.  J Neurosci. 1997;  17 6783-6797
• 50 Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome.  Nat Genet. 1997;  15 70-73
• 51 Kleijnen M F, Shih A H, Zhou P, Kumar S, Soccio R E, Kedersha N L, Gill G, Howley P M. The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome.  Mol Cell. 2000;  6 409-419
• 52 Kneussel M. Dynamic regulation of GABA_A receptors at synaptic sites.  Brain Res Rev. 2002;  39 74-83
• 53 Kyriakides T, Hallam L A, Hockey A, Silberstein P, Kakulas B A. Angelman's syndrome: a neuropathological study.  Acta Neuropathol (Berlin). 1992;  83 675-678
• 54 Laan L AEM, Renier W O, Frans W, Buntinx I M, Burgt I JAM, Stroink H. Zwinderman KH, van Dijk JG, Bouwer OF. Evolution of epilepsy and EEG findings in Angelman syndrome.  Epilepsia. 1997;  38 195-199
• 55 Laan L AEM, Halley D J, den Boer A T, Hennekam R, Renier W O. Brouwer OF. Angelman syndrome without detectable chromosome 15 q11 - 13 anomaly: clinical study of familial and isolated cases.  Am J Med Genet. 1998;  76 262-268
• 56 Laan L AEM, v Haeringen A, Brouwer O F. Angelman syndrome: a review of clinical and genetic aspects.  Clin Neurol Neurosurg. 1999;  101 161-170
• 57 Lalande M, Minassian B A, DeLorey T M, Olsen R W. Parental imprinting and Angelman syndrome. Delgado-Escueta AV, Wilson WA, Olsen RW, Porter RJ Jasper's Basic Mechanisms of the Epilepsies. 3rd ed. Adv. Neurol. 79. Philadelphia; Lippincott Williams and Wilkins 1999: 421-429
• 58 Lossie A C, Whitney M M, Amidon D, Dong H J, Chen P, Theriaque D, Hutson A, Nicholls R D, Zori R T, Williams C A, Driscoll D J. Distinct phenotypes distinguish the molecular classes of Angelman syndrome.  J Med Genet. 2001;  38 834-845
• 59 Matsumoto A, Kumagai, Miura K, Miyazaki S, Hayakawa C, Yamanaka T. Epilepsy in Angelman syndrome associated with chromosome 15q deletion.  Epilepsia. 1992;  33 1083-1090
• 60 Meguro M, Kashiwagi A, Mitsuya K, Nakao M, Kondo I, Saitoh S, Oshimura M. A novel maternally expressed gene, ATP10 C, encodes a putative aminophospholipid translocase associated with Angelman syndrome.  Nat Genet. 2001;  28 19-20
• 61 Minassian B A, DeLorey T M, Olsen R W. et al . GABRB3 gene: a gene involved in the epilepsy of Angelman syndrome.  Abs Soc Hum Genet. 1996;  59 A273
• 62 Minassian B A, DeLorey T M, Olsen R W, Philippart M, Bronstein Y, Zhang Q, Guerrini R, van Ness P, Livet M O, Delagado-Escueta A V. Angelman syndrome: correlations between epilepsy phenotypes and genotypes.  Ann Neurol. 1998;  43 485-493
• 63 Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes G L, Wagstaff J. Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice.  Neurobiol Dis. 2002;  9 149-159
• 64 Moncla A, Malzac P, Voelckel M A, Auquier P, Girardot L, Mattei M G, Philip N, Mattei J F, Lalande M, Livet M O. Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients.  Eur J Hum Genet. 1999;  7 131-139
• 65 Odano I, Anezaki T, Ohkubo M, Yonekura Y, Onishi Y, Inuzuka T, Takahashi M, Tsugi S. Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazemil and single-photon emission tomography.  Eur J Nucl Med. 1996;  23 598-604
• 66 Østergaard 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;  43 718-719
• 67 Pampiglione G, Martinez A. Evolution of Angelman syndrome: follow-up of 3 new cases.  Electroencephalogr Clin Neurophysiol. 1983;  56 72P
• 68 Rees J. Complex disease and the new clinical sciences.  Science. 2002;  296 698-701
• 69 Rivera C, Voipio J, Payne J A, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K. The K⁺/Cl^- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation.  Nature. 1999;  397 251-255
• 70 Rougeulle C, Glatt H, Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain.  Nat Genet. 1997;  17 14-15
• 71 Rubin D I, Patterson M C, Westmoreland B F, Klass D W. Angelman's syndrome: clinical and electroencephalographic findings.  Electroencephalogr Clin Neurophysiol. 1997;  102 299-302
• 72 Ruggieri M, McShane M A. Parental view of epilepsy in Angelman syndrome: a questionnaire study.  Arch Dis Child. 1998;  79 423-426
• 73 Sandanam T, Beange H, Robson L, Woolnough H, Buchholtz T, Smith A. Manifestations in institutionalized adults with Angelman syndrome due to deletion.  Am J Med Genet. 1997;  70 415-420
• 74 Singer W. Neuronal synchrony: a versatile code for the definition of relations?.  Neuron. 1999;  24 49-65 111-125
• 75 Sinkkonen S T, Homanics G E, Korpi E R. Mouse models of Angelman syndrome, a neurodevelopmental disorder, display different brain regional GABA_A receptor alterations.  Neurosci Lett. 2003;  340 205-208
• 76 Staak R, Pape H C. Contribution of GABA_A and GABA_B receptors to thalamic neuronal activity during spontaneous absence seizures in rats.  J Neurosci. 2001;  21 1378-1384
• 77 Strohman R. Maneuvering in the complex path from genotype to phenotype.  Science. 2002;  296 701-703
• 78 Sugimoto T, Yasuhara A, Ohta T, Nishida N, Saitoh S, Hamabe J, Niikawa N. Angelman syndrome in 3 siblings: characteristic epileptic seizures and EEG abnormalities.  Epilepsia. 1992;  33 1078-1082
• 79 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 1518-1519
• 80 Van Buggenhout G J, Descheemaeker M J, Thiry P, Trommelen J C, Hamel B C, Fryns J P. Angelman syndrome in three adult patients with atypical presentation and severe neurological complications.  Genet Couns. 2000;  11 363-373
• 81 Viani F, Romeo A, Viri M, Mastrangelo M, Lalatta F, Selicorni A, Gobbi G, Lanzi G, Bettio D, Briscioli V, Di Segni M, Parini R, Terzoli G. Seizures and EEG patterns in Angelman's syndrome.  J Child Neurol. 1995;  10 467-471
• 82 Wagstaff J, Knoll J H, Flemming J, Kirkness E F, Martin-Gallardo A, Greenberg F, Graham J M, Meninger J, Ward D, Venter J C, Lalande M. Localization of the gene encoding the GABAA receptor beta3 subunit to the Angelman/Prader-Willi region of human chromosome 15.  Am J Hum Genet. 1991;  49 330-337
• 83 Wang J F, Sun X, Chen B, Young L T. Lamotrigine increases gene expression of GABA-A receptor β3 subunit in primary cultured rat hippocampal cells. Neuropsychopharmacol.  . 2002;  26 415-421
• 84 Weeber E J, Jiang Y H, Elgersma Y, Varga A W, Carrasquillo Y, Brown S E, Christian J M, Mirnikjoo B, Silva A, Beaudet A L, Sweatt J D. Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome.  J Neurosci. 2003;  23 2634-2644
• 85 Whiting S, Duchowny M. Clinical spectrum of cortical dysplasia in childhood: diagnosis and treatment issues.  J Child Neurol. 1999;  14 759-771
• 86 Williams C A, Angelman H, Clayton-Smith J, Driscoll D J, Hendrickson J E, Knoll J H, Magenis R E, Schinzel A, Wagstaff J, Whidden E M, Zori R. Angelman syndrome: consensus for diagnostic criteria.  Am J Med Genet. 1995;  56 237-238