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Angelman syndrome Correlations between epilepsy phenotypes and genotypes.

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Angelman Syndrome: Correlations between
Epilepsy Phenotypes and Genotypes
Berge A. Minassian, MD,*t$ Timothy M. DeLorey, PhD,s Richard W. Olsen, PhD,§ Michel Philippart, MD,S
Yuri Bronstein, M D , t Quanwei Zhang, MD,*f Renzo Guerrini, MD," Paul Van Ness, MD,#
Marie 0. Livet, MD,** and Antonio V. Delgado-Escueta, MD't
We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS), including chromosome 15qll-13 deletions (class I), uniparental disomy (class 11), methylation imprinting abnormalities (class 111), and mutation in the
UBE3A gene (class IV). Twenty patients were prospectively selected based on clinical cytogenetic and molecular diagnosis
of AS. All patients had 6 to 72 hours of closed-circuit television videotaping and digitized electroencephalogrpahic (EEG)
telemetry. Patients from all genotypic classes had characteristic EEGs with diffuse bifrontally dominant high-amplitude
1- to 3-Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves. Class I patients had severe intractable
epilepsy, most frequently with atypical absences and myoclonias and less frequently with generalized extensor tonic
seizures or flexor spasms. Epileptic spasms were recorded in AS patients as old as 41 years. Aged-matched class 11, 111,
and IV patients had either no epilepsy or drug-responsive mild epilepsy with relatively infrequent atypical absences,
myoclonias, or atonic seizures. In conclusion, maternally inherited chromosome 15qll-13 deletions produce severe epilepsy. Loss-of-function UBE3A mutations, uniparental disomy, or methylation imprint abnormalities in AS are associated with relatively mild epilepsy. Involvement of other genes in the chromosome 15qll-13 deletion, such as GABRB3,
may explain severe epilepsy in AS.
Minassian BA, DeLorey TM, Olsen RW, Philippart M, Bronstein Y, Zhang Q, Guerrini R, Van Ness P,
Livet MO, Delgado-Escueta AV. Angelman syndrome: correlations between epilepsy
phenotypes and genotypes. Ann Neurol 1998;43:485-493
Angelman syndrome (AS) is characterized by global arrest in neurological development. The child (or adult)
with AS functions as a I-year-old infant, has no language, and has a happy demeanor with excessive laughter. The wide-based gait, with arms held up and flexed
at the elbow, resembles that of a newly walking toddler. This phenotype, along with jerky movements,
when seen in the child, adolescent, or adult resembles a
"happy puppet" on a string.' Other clinical features,
originally described by Angelman, in 1965, include microcephaly, flat occiput, hypopigmentation, apparent
prognathism, frequent tongue protrusions, strabismus,
and seizures.* ,2
Most AS cases (70%) are caused by large (4 Mb) maternally inherited deletions in chromosome 15qll-13
(class I). Genes encompassed in this deletion include
three y-aminobutyrate-A (GABA,) receptor subunit
genes, GABRBS, GABRA5, and GABRG3 (GAB&),
and the UBE3A gene (Fig 1). These deletions have
From the *Comprehensive Epilepsy Program, Department of Neurology, §Department of Molecular and Medical Pharmacology, and
YDivision of Pediatric Neurology, University of California, Los Angeles, School of Medicine, and tNeurology and Research Semites,
West Los Angeles DVA Medical Center, Los Angeles, CA; $Division of Neurology, Department of Pediatrics, Hospital for Sick
Children and Bloorview Epilepsy Program, University of Toronto,
Toronto, Ontario, Canada; "Institute of Child Neurology and Psychiatry, University of Pisa and IRCCS Stella Maris Foundation,
common centromeric and telomeric breakpoints in
most
AS-related genes seem to be exclusively
expressed from the maternally inherited chromosome
15qll-13 region. This phenomenon is termed imprinting. The same deletion occurring in the paternal
germline results in a distinctly different condition,
the Prader-Willi syndrome (PWS). Another feature
of imprinting is that the pattern of methylation of a
number of CpG islands in the region is different on
the maternal chromosome versus the paternal chrornosome (eg, at loci PW71 and SNRl", see Fig l).5
Rare cases of AS are due to paternal uniparental disomy (UPD) in which both 15qll-13 chromosomal
regions are inherited from the father with no maternal
contribution for this region and thus no expression of
the AS gene(s) (class II).6 Cases in which the methylation pattern of the maternal 15qll-13 region is abnormal (paternal methylation pattern on the maternal
chromosome) (class 111) are just as rare. These cases are
Pisa, Italy; #Neurology Department, University of Texas, Dallas,
TX;and **Departmentof Child Neurology, Hopital dEnfants de la
Timone, Marseille, France.
Received Aug 12, 1997, and in revised form Nov
pub,ication Nov 11, 1997.
Accepted for
Address correspondence to Dr Delgado-Escueta, Comprehensive
Epilepsy Program, UCLA, Building 500, Room 3405, 11301
Wilshire Boulevard, Los Angeles, CA 90073.
Copyright 0 1998 by the American Neurological Association 485
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AS or PWS common deletion
frequently associated with small deletions in the imprinting center (IC), approximately 1.5 Mb centromeric to the GABAR gene cluster (see Fig 1). The IC
is thought to control methylation patterns and imprinting.'~~Whether imprinting by the IC extends as
far as the GABAR cluster is not clear, but imprinting
effects in the form of differential DNA replication timing on the maternal versus the paternal chromosomes
have been suggested near the promoter regions of
GABRB3 and GABRA5.9
The other AS cases (about 25%) have none of the
above abnormalities and have been classified as class IV.
Most recently, mutations in the gene UBE3A have been
found in some patients (about 20%) from this class.'""'
IC may also control expression of UBE3A, which is approximately 0.5 Mb telomeric to it (see Fig 1).
Our present study examines the epilepsy of patients
from the four classes described. Patients with clinical features resembling AS but without molecular verification were not included in this study. The electroencephalographs (EEGs) and epilepsy of AS have
been studied previously,' 2p21 but epilepsy phenotypesgenotype correlations were not performed. Because different genetic alterations can result in AS (eg, single
base mutation in UBE3A versus a 4-million base-pair
deletion) and because candidate genes for epilepsy
(GABARs) are present within the 15qll-13 deletion, it
is important to determine whether differences in the
electroclinical phenotypes exist among the different
molecular classes of AS.
Patients and Methods
Patients
Nine patients with AS had large chromosome 15qll-13 deletions (class I). Their ages were 2, 3, 6, 9, l l , 15, 29, 38,
and 41 years. Four patients (ages 7, 7, 15, and 15 years) had
paternal UPD (class 11). Five patients (ages 6, 6, 13, 15, and
24 years) had methylation imprint abnormalities (class 111).
There were two patients (ages 10 and 15 years) with proven
loss-of-function UBE3A mutations (class IV). Patients were
recruited from among the membership of the Angelman
Syndrome Foundation (USA), from a chronic care facility
486
Annals of Neurology
Vol 43
No 4
April 1998
Fig 1. Map of Angelman syndrome (AS)
region (not to scale). UBE3A, Ubiquitin
protein ligase gene (mutations resulting
in AS fDund in this gene); IC, imprinting center; GABRB3, GABRAS, and
GABRG3, GABAA receptor subunit genes;
PW71 and SNRPN two sites ofparentof-origin speci$c methylation; D15S144, a
microsatellite locus; P WS, Prader- Willi
syndrome region; S, maternal deletion in a
family with AS with a severe epilepsy17
Gee Discussion) encompassing UBE3A and
part of GABRB3.
for developmental disorders in Los Angeles, or from the
clinic. Patient selection was based on the clinical diagnosis of
AS and on genetic class. Selection was not based on seizure
status. Informed consent was obtained from parents or
guardians in all cases.
Closed-Circuit Television videotaping and Digitized
EEG Telemetry (CCW-EEG)
EEGs were recorded through scalp Ag-AgC1 or gold disc
electrodes applied with colloidion paste and positioned according to the International 10-20 system. Continuous intensive monitoring and synchronization of the clinical and
EEG states was carried out using the BMSI 4000 or 5000
systems. Six to 72 hours of CCTV-EEG monitoring in the
awake and sleep states was performed.
Genetic Status Ascertainment
All AS cases satisfied consensus clinical diagnostic criteria.'
To confirm deletion, including deletion of the GABRB3
gene in class I patients, loss of heterozygosity was assessed by
genotyping patients and their parents for polymorphic microsatellite markers spanning the commonly deleted segment
of 15qll-13 including markers from within and around the
GABRB3 gene (D15Sl1, D15S128, D15S210, D15S122,
D15S10, D15S113, D15S1234, GABRB3, D15S97,
155CA1, 155CA2, 85CA1, GABRA5, D15S156, and
D15S165). The methods for polymerase chain reaction are
described by Weber and May.22 UPD cases (class 11) were
confirmed by fluorescent in situ hybridization using probes
D15S10 and GABRB3 from ONCOR. Genetic status of
two UPD cases has been reported previously." Confirmation
of methylation imprint abnormality (class 111) and absence of
methylation imprint abnormality (class Iv) was determined
by demonstrating biparental inheritance using genotyping
followed by Southern blot analysis. Briefly, genornic DNA
from the proband and the parents was digested with restriction enzymes XbaI and Not1 and probed with the SNRPN
probe and digested with Hind111 and HpaII and probed with
PW71B.8 The mutation in 1 class IV patient (ASOO) has
been described previously (patient WB141)." The other
class IV patient's (AS4) loss-of-function mutation was discovered by Fang and co-workers and will be described separately by these authors (P. Fang, A. Beaudet, personal communication, 1997).
Results
Interictal Awake and Sleep EEG
Awake EEG background activities of children with
chromosome 15qll-13 deletions were slow for age.
Distinctive trains of diffuse high-amplitude 1- to 3-Hz
triphasic or polyphasic slow waves were frequently
seen, accentuated in the frontal regions bilaterally.
When anteroposterior bipolar montages are used, these
often appear as notched negative slow waves. The
notch is on the downslope of the slow wave and may
separate itself out into a sharp wave or a spike while
maintaining a closer temporal proximity to the preceding rather than to the subsequent slow wave. To distinguish them from spike and slow wave complexes, we
refer to this pattern as slow and sharp waves or slow
and spike waves (Table 1 and Fig 2).
The youngest patient (age 2 years) had typical hypsarrhythmia. The 3- to 1I-year-old patients had 2- to
3-Hz slow background rhythms with independent multifocal spikes predominantly in the frontal and temporal head regions, runs of rapid spikes, and paroxysmal
1.5- to 3-Hz slow waves mixed with spikes resembling
the EEG of Lennox-Gastaut syndrome.
One I5-year-old patient with deletion had striking
hypnagogic hypersynchrony, which is not expected to
be seen beyond 6 years of age.
In all class I cases, more so in younger children, bifrontally dominant high-amplitude 2- to 3-Hz slow
and sharp waves burst frequently, lasting 2 to 10 seconds but with no detectable signs of a clinical seizure.
In all class I children, 2- to 3-Hz slow and sharp waves
burst in even more prolonged runs during the onset of
stage 2 sleep (see Fig 2). During rapid eye movement
sleep, a marked reduction, if not total disappearance, of
paroxysmal slow waves and slow and spike wave formations occurred. In all class I children, passive or active eye closure produced rhythmic runs of monomorphic medium- and high-amplitude (>20O mV) 4-Hz
sharp waves rarely mixed with spikes posteriorly (see
Table 1).
In contrast, all three adults with deletions had EEG
background activities appropriate for age. However,
frequent bursts of generalized irregular 2- to 4-Hz slow
and spike waves appeared during wakefulness and
sleep.
Runs of notched slow waves and especially bursts of
slow and sharp waves were less frequent in class I1 and
I11 patients than in age-matched patients with deletions. Similarly, the EEG background and the sleep
features were more organized in classes I1 and I11 compared with class I (Tables 2 and 3).
In the class IV patients, the EEG background was
normal (see Table 3). Rare slow waves or irregular
spike and wave bursts occurred during wakefulness;
such runs of bifrontally prominent notched slow waves
or slow and sharp waves appeared more often during
sleep.
Among the 20 cases, 0/9 in class I but 8/11 in other
classes (3/4 in class 11, 3/5 in class 111, and 2/2 in class
IV) had normal EEG background.
Seizures Reported by Parents or Caretakers
Parents and
caretakers witnessed epileptic seizures in all 9 patients.
All were reported to have brief staring spells with or
without head nods lasting a few seconds, multiple
times daily. Five patients had brief, split-second, generalized “shuddering” seizures, multiple times daily. Six
patients had less frequent atonic seizures (drop attacks).
Flexor or extensor spasms were reported in 4 patients.
Two patients were witnessed to have nocturnal tonic
seizures. Seven patients had had repeated prolonged episodes of atypical absence, tonic, or tonic-clonic status
epilepticus. None of the adults had been thought to
still have seizures, although seizures were recorded in
all 3 during this study. All 7 children with deletion
were on monotherapy or polytherapy with phenytoin,
valproic acid, clobazam, lamotrigine, and clonazepam.
The adults were not on any antiepileptic drugs.
CLASS I, DELETION CASES (SEE TABLE I).
CLASS 11, UPD CASES (SEE TABLE 2). Two of 4 patients
were thought not to have seizures. Of the 2 with seizures, 1 had had myoclonic seizures and the other had
absences and myoclonic seizures. The second patient
was taking valproic acid, clobazam, and lorazepam.
CLASS 111, METHYLATION IMPRINT ABNORMALITY CASES
(SEE TABLE 3). Three children (ages 6, 6, and 13 years)
were thought not to ever have had seizures and were
not on medications. One 24-year old (ASllO), whom
we had started studying at age 15 years, had had rare
staring spells and mild myoclonias and has been free of
seizures for 8 years on a combination of valproic acid
and ethosuximide. The other 24-year old, who was on
carbamazepine, had frequent ongoing absences and
tonic and atonic seizures.
One
child had had staring spells and two generalized tonic
convulsions. She was considered free of seizures at age
10 while on valproic acid. The other child was considered not to have had seizures at the time we studied
her at age 15. She had her first generalized tonic seizure 3 years later.
CLASS IV, WITH UBE3A MUTATION (SEE TABLE 3).
Seizure ljpes and Ictal EEG Recorded During
CCTV-EEG Monitoring
CLASS I (TABLE 4). All 6 children and 2 of the 3 adults
had atypical absences that consisted of 2- to 10-second
periods of arrest activity, with flickering of the eyelids,
Minassian et al: Epilepsy in Angelman Syndrome 487
Table 1. Angelman Syndrome: History of Epilepsy Phenotypes in Chromosome 15911-13 Deletions
Family
No.
Class
Age
(yr)/Sex
Seizure Reported on History
Interictal EEG
Response to Antiepileptic Drugs
Slow background of EEG with
triphasic 2- to 3-Hz delta
slowing
Bursts of diffuse 2-Hz slow spike
waves and multifocal spikes
Continuous 2-Hz slow and spike
waves during slow wave sleep
Hypnogognic theta rhythms
Slow background of EEG with
triphasic 2- to 3-Hz delta
slowing
Bursts of slow spike waves and
multifocal spikes
Mild disorganization of background with 9- to 10-Hz alpha rhythms mixed with 6- to
7-Hz theta slowing diffusely
Bursts of 1- to 2-Hz delta slow
waves, prominent anteriorly
Bursts of diffuse 2-Hz slow and
spike waves occur only during
sleep
Slow background of EEG with
triphasic 2- to 3-Hz delta
slowing
Bursts of slow spike waves and
multifocal spikes
Lamotrigine or clobazam: poor
response
Vomiting with ethosuximide
Tonic seizures persist especially
during sleep
Mildly disorganized background
8-Hz activities mixed with
6-Hz waves
Bursts of diffuse 2.5 Hz slowing
mixed with spikes
Disorganized background of 9and 5-Hz waves
Bursts of 1- to 2-Hz triphasic
slow waves with spikes mixed
in between slow waves
Slow background of EEG with
triphasic 2- to 3-Hz delta
slowing
Bursts of slow spike waves and
multifocal spikes
Phenytoin, phenobarbital and
clorazepate: poor response
As2
15/M
Atypical absences with staring
and arrest of activities; nocturnal tonic seizures; myoclonic
seizures and atypical absence
status
AS3
11/F
Tonic status epilepticus at onset at
2 yr of age; tonic spasms;
atypical absences; myoclonic
seizures, drop attacks
As7
38/F
Atypical absences with eye blinks;
at times head and eye deviation to the left; recurred until
age 33 to 35 yr; convulsive
status epilepticus for 4 hr at 2
yr and again at 2.5 yr
AS1 1
6JM
AS27
41/F
Atypical absences with fomard or
backward head drops and eye
blinks at 6 mo of age; tonic
spasms; atonic drop seizures at
18 mo; myoclonic status at 1
yr of age and absence status at
3 yr of age
Atypical absences with eyes rolling up or head nods; aronic
drop seizures; myoclonic seizures; tonic extensor spasms
As33
29lF
AS38
3lM
AS52
2/F
AS70
9/M
Flexor spasms; nocturnal tonic
(few seconds of clonic) seizures; atonic drop seizures;
atypical absences with head
nods
Atypical absences with head drop
and shoulder droop at 6 mo
of age; atonic drop seizures at
14 mo of age; tonic convulsive
status and atypical absence status at 15 mo
Atypical absences and atonic drop
seizures at 8 mo; generalized
tonic status epilepticus and frequent myoclonic seizures;
tonic spasms during nocturnal
sleep
Atypical absence status epilepticus
at 12 mo; repeated episodes of
convulsive and nonconvulsive
status epilepticus; frequent
atonic, myoclonic, atypical
absence and generalized tonicclonic seizures
488 Annals of Neurology Vol 43 No 4 April 1998
Disorganized 6- to 8-Hz slowing
mixed with arrhythmic 1- to
2-Hz slow waves and 18- to
22-Hz low voltage fast
activities
Bursts of 2- to 3-Hz slow waves,
frequently mixed with spikes
to form slow spike waves that
continue for 25 sec
Disorganized 5- to 7-Hz slowing
with arrhythmic 1- to 2-Hz
slow waves
Bursts of diffuse 2- to 3-Hz slow
waves, frequently mixed with
spikes to form slow spike
waves
Phenytoin, valproate, and clonazepam: poor response
Phenytoin and phenobarbital:
poor response
Seizures were reported to stop at
age 35 yr, but CCW-EEG at
38 years recorded atypical
a bsences.
Lamotrigine, prednisone, phenytoin, felbamate, phenobarbital,
clonazepam, valproate: poor
response
Clorazepate, valproate: poor
response
Phenytoin and valproate: poor
response
Clonazepam and ketogenic diet:
good response
Phenytoin-induced convulsive
status; clonazepam reduced
absences; lorazepam is required
to stop frequent convulsive
status.
Phenytoin-induced nonconvulsive
status epilepticus
Presently on lamotrigine and
clobazam, no longer has status; continues to have frequent
atypical absence and myoclonic seizures.
Fig 2. Bifiontally dominant continuous polyphasic slow waves during sleep in an I I-year-old girl with AS with a deletion
(on phenytoin).
Tabke 2. Angelman Syndrome: History of Epilepsy Phenotypes in Uniparental Disomy
Family
No.
Class
Age
(yr)/Sex
Seizure Reported on History
Interictal EEG
Response to Antiepileptic Drugs
None
Slow background of awake EEG with
triphasic delta 2- to 3-Hz slowing
Bursts of 2-Hz slow spike waves
Normal EEG background
Normal EEG background
Bursts of 2-Hz slow spike waves
Normal EEG background
Bursts of 2-Hz slow spike waves
No treatment
~~
AS20
I1
8/M
AS80
AS90
I1
I1
15lM
71M
None
Myoclonic seizures
Asinn
11
15/M
Infrequent myoclonic seizures
and absences
glazed eyes, and lip smacking. Four patients had atonia
of neck and shoulders. The associated EEG showed
diffuse, bilaterally synchronous, paroxysmal bursts of
high-amplitude, rhythmic, irregular slow spike waves
(see Table 1). Atypical absence attacks were very frequent, sometimes occurring up to 50 times a day (less
frequent in the adults). The diffuse paroxysms were
sometimes followed by diffuse EEG attenuation as the
patient remained motionless. In 4 patients, diminished
neck and facial muscle tonic would cause the patient to
nod the head downward, open mouthed, several times
during atypical absence episodes. Generalized EEG
slowing was suddenly replaced by low-voltage fast
rhythms or a diffuse electrodecremental pattern.
Four class I patients had sudden atonic falls or
No treatment
No treatment
Decreased seizures on a combination of valproate, clobazam, and lorazepam
atonic drop seizures during diffuse EEG flattening with
low-voltage, fast 20- to 3 0 - H ~rhythms.
Seven class I patients had generalized tonic extension
and upward elevation of the upper limbs with truncal
or axial rigidity during EEG diffuse flattening. Many
of these tonic seizures were short, lasting 4 to 10 seconds, and were associated with apnea and facial grimacing. Three of these patients also had flexor spasms
or salaam seizures with forward thrusting of the body
along with flexion of the neck and arms (see Table 4).
All but 1 patient with deletion had massive myoclonic seizures consisting of a split-second whole-body
shudder, associated with bursts of high-amplitude irregular spikes and slow waves. Of the children with
deletion, the oldest (age 15) was on no medications
Minassian et al: Epilepsy in Angelman Syndrome 489
Table 3. Angelman Syndrome: History of Epilepsy Phenotypes in Metbylation Imprinting Abnormalities and UBE3A Mutation
~
Familv
No.
Class
Age (yr)/ Seizure Reported on
History
sevx
"
Interictal EEG
Response to
Antiepileptic Drugs
~
AS50
111
24lM
AS60
I11
GIM
AS43A
AS43B
111
I11
61F
131F
AS110
I11
15lM
AS00
IV (UBE3A 101F
Mutation)
IV (UBE3A 18lF
Mutation)
AS4
Increased frequency of
Atypical absences with head Normal EEG background
atypical absences, tonic
Bursts of 2- to 2.5-Hz slow spike
nodding; generalized
spasms and flexor
tonic spasms; infrequent
waves
spasms with increased
atonic drop seizures
doses of carbamazepine. Improved with
carbamazepine withdrawal.
Slow background of awake EEG No treatment
None
with triphasic 2- to 3-Hz delta
slowing
Normal awake EEG background No treatment
None
Normal awake EEG background No treatment
None
2-Hz slow spike-waves in sleep
Seizure free on a combiAtypical absences and myo- Slow background
nation of valproate
Bursts of 2-Hz slow and spike
clonic seizures
and ethosuximide
waves
Normal awake EEG background Valproate: good response
Atypical absences; infre2-Hz slow spike waves in sleep
quent tonic seizures
No treatment until 18 yr
Normal awake background of
None until 18 yr of age
of age when valproate
EEG with 9 to 11 Hz; prowhen one generalized
was started
longed bursts of triphasic 2- to
tonic seizure appeared;
3-Hz slowing interrupt stages
rare atypical absences
with shoulder slump
2 and 3 sleep
Bursts of 1- to 2-Hz slow spike
and lip smacking were
waves and multifocal spikes
suspected
and had the fewest seizures (atypical absence, myoclonic, and tonic).
CLASS 11 (TABLE 5).
Epileptic seizures were recorded in
3 of 4 patients, including 1 in whom seizures had
never been suspected. The seizures were atypical absences and myoclonic seizures and atonic falls similar
to those described previously. Seizures in this class were
less frequent than in class I patients.
One 6-year-old child, with
methylation imprint abnormality at both PW71 and
SNRI", had infrequent atypical absences and myoclonic seizures. He was on no medications. The other
6-year old and the 13-year old had no seizures except
for one atypical absence with EEG desynchrony in the
13-year old during 36 hours of recording. Neither was
taking medications. A 24-year old (AS110) on valproic
acid and ethosuximide was free of seizures. A 24-year
old on carbamazepine had frequent atypical absences,
atonic head drops, tonic seizures, flexor spasms, and
myoclonic seizures.
CLASS 111 (SEE TABLE 5).
CLASS IV (SEE TABLE 5). Rare myoclonic jerks were recorded in both children associated with diffuse paroxysms of slow waves mixed with spikes. During 36
hours of recording, the 15-year old had a single atypical absence with EEG desynchrony.
490
Annals of Neurology Vol 43
No 4
April 1998
Discussion
Angelman syndrome is known primarily as a common
cause of profound mental retardation. With an incidence of 1:10,000,23 it is not an uncommon cause of
epilepsy.
The most common seizure types reported by caregivers and verified by CCTV-EEG recordings in this
study are atypical absences and myoclonic seizures.
This was also stated by Viani and associates." In addition, CCTV-EEG also captured atonic, generalized
extensor tonic, flexor spasms, and secondary generalized tonic-clonic seizures. Salaam seizures or flexor
spasms are characteristic features of West syndrome
(infantile spasms); and the constellation of atypical absences and myoclonic, atonic drop, and extensor tonic
seizures chpracterizes Lennox-Gastaut syndrome. These
two epilepsies are believed to represent developmental
stage-specific common end results of a variety of insults
to the brain. Several of our patients with deletions and
I class 111 patient on carbamazepine had flexor spasms
past the chronological stage of infancy (ages 3, 5, 15,
29, and 41). Children and adults with AS might,
therefore, be considered to retain the networks and systems within the central nervous system that can only
express epilepsy phenotypes of infancy and early childhood.
The interictal EEG of AS is highly characteristic and
shows bifrontally dominant rhythmic runs of notched
Table 4. Angelman Syndrome with Chromosome 15qll-13 Deletions: Epilepy Phenotypes on CCTV-EEG Telemety
Family No.
AS2
AS3
AS7
AS11
AS27
AS33
AS38
AS52
AS70
I
I
I
I
I
I
I
I
I
X
x
x
X
X
X
X
X
X
X
Molecular Diagnosis Class
Phenotypes
Atypical absence with irregular 2- to
3-Hz spike and slow waves:
Impaired responsiveness, stare, arrest,
eye blinking
Atonia of neck and shoulder (head
nods)
Atypical absence with EEG desynchrony"
Atonic falls or drop seizures with EEG
desynchrony"
Tonic spasms with EEG desynchrony"
Flexor spasms or "salaam seizures" with
EEG spike waves andlor desynchrony'
Myoclonic seizures during irregular 2- to
3-Hz spike and slow waves
Secondary tonic clonic seizures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
?b
X
X
X
X
X
X
X
X
X
X
X
"EEG desynchrony is identical to diffuse EEG flattening with low voltage fast activities (18 to 25 Hz) or the so-called electrodecremental
'.Zr:i
suspicious attacks.
Table 5.Angelman Syndrome: Epilepsy Phenotypes on CCTV-EEG Telemetry
Family No.
Molecular Diagnosis Class
Phenotypes
Atypical absence with irregular 2- to
3-Hz spike and slow waves:
Impaired responsiveness, stare, arrest,
eye blinking
Atonic of neck and shoulder (head
nods)
Atypical absence with EEG desynchronya
Atonic falls or drop seizures with EEG
desynchrony"
Tonic spasms with EEG desynchrony"
Flexor spasms or "salaam seizures" with
EEG spike waves and/or desynchrony"
Myoclonic seizures during irregular 2- to
3-Hz spike and slow waves
Secondary tonic clonic seizures
AS20 AS80 AS90 AS100 AS110 AS50 AS60 AS43A AS43B AS4 AS00
I1
I1
X
I11
111
I11
x
x
xb
X
X
I1
I1
x
111
I11
IV
IV
Xb
xb
X
X
X
X
x
x
x
xb
"EEG desynchrony is identical to diffuse EEG flattening with low voltage fast activities (18 to 25 Hz) or the so-called electrodecremental
attern.
k a r e seizures: two or three attacks in 36 hours of CCTV-EEG.
'One atypical absence attack recorded with or without head nods in 36 hours.
slow waves or slow and sharp waves, especially during
sleep. These might be difficult to detect without a sleep
EEG. These slow and sharp waves frequently are continuous during sleep, taking up to 50 to 80% of stages
3 and 4 sleep, thus resembling continuous spike and
slow waves during sleep. However, they differ in morphology from the continuous spike and slow waves
seen in Landau-Kleffner syndrome and may help dif-
ferentiate AS from Landau-Kleffner syndrome in the
context of an epileptic child with no language.
Our findings of maturational changes in the EEG
background are in agreement with the observations of
Matsumoto and colleague^.'^ The youngest child we
studied (age 2) had an EEG reminiscent of hypsarrhythmia, and the preadolescent children's EEGs resemble those of Lennox-Gastaut. In adults, the EEG
Minassian et al: Epilepsy in Angelman Syndrome
491
background normalizes, as also observed by Boyd and
co-workers.I2 However, closer examination with longterm CCTV-EEG revealed numerous paroxysms, frequently associated with seizures.
CCTV-EEG was useful in determining the frequency and type of seizures. The frequency of atypical
absences in class I patients (8/9, 4 with atonia) and
their infrequent episodes in other classes (5/11, 2 with
atonic) were underestimated by caregivers (see Tables 4
and 5). The frequency of myoclonic seizures (8/9 class
I and 7/11 classes 11, 111, and IV) was similar to that
described by Guerrini and colleagues.” We also observed examples of atonic drop (4/9 class I, 1 class 11),
tonic extension spasms (7/9 class I, 1 class 111), and
flexor spasms (4/9 class I, I class 111) independent of
atypical absence attacks.
A number of different medications had been prescribed for epilepsy treatment in class I children. Seizure control was best with either valproic acid or clonazepam; however, seizures were still occurring in all, as
shown by CCTV-EEG. One 11-year-old child appeared worse on phenytoin. Her EEG features and frequency and severity of seizures, including continuous
slow and sharp waves during sleep, were worse than
any of the other children including those younger. The
9-year-old class I child had previously been on phenytoin and carbamazepine and had developed atypical absence status epilepticus and convulsive status epilepticus on both medications. One adult from class I11 had
multiple seizures on carbamazepine that decreased dramatically when we stopped his medication. Similar observations were made by Laan and associate^.'^
This study shows that patients with genetically confirmed AS of all classes and ages can generate the characteristic runs of notched slow waves (Fig 2). Importantly, although the UBE3A mutation children (class
IV) and most of the class I1 and I11 children have epilepsy (see Table 2), their epilepsy phenotype is less severe (compare Tables 4 and 5).’* Relatively infrequent
atypical absences, myoclonic seizures, and rare atonic
falls were recorded in patients from classes 11, 111, and
IV. Seizures are frequently unnoticed by parents and
easier to control. With the exception of 1 patient on
carbamazepine, none had salaam seizures or tonic seizures. Two patients had the methylation imprint abnormality restricted to the SNRF” locus. These 2
seem to have milder or no epilepsy compared with
those with abnormalities at both PW71 and SNRF”
loci (AS43A and AS43B in the tables). Whether this
finding is significant awaits corroboration.’
More severe epilepsy in deletion cases would indicate
that genes other than UBE3A may contribute to intractable epilepsy of deletion cases. consistent with the
possibility of a multigene syndrome, other studies have
noted diversity in other phenotypic features between
492 Annals of Neurology Vol 43 No 4 April 1998
classes, such as microcephaly and hypopigmentation
in AS.25
Among the genes present in the large chromosome
15qll-13 deletion of class I AS patients are a cluster of
three GABA, receptor subunits. Disruption of inhibitory synaptic function involving GABA has long been
suspected to play a role in epilepsy and perhaps other
neurological/neurodevelopmental disorders. GABRB3
is the most centromeric of the three GABARs (see Fig
1). It is suspected to play a role in AS because it is the
only one of the three subunit genes that is deleted (partially) in 4 children with AS from two different families with overlapping microdeletions (- 1 Mb), encompassing UBE3A and GABRB3 but sparing GABRA5
and GABRG3. The electroclinical phenotypes of these
children is as severe as that of our patients with the
common large d e l e t i ~ n ~ ~ ”(see
, ’ ~Fig 1).
We hypothesize that deletion of GABRB3, when
combined with faulty expression of maternal UBE3A,
results in the severe epilepsy of class I AS patients. The
absence of seizures or of abnormal EEGs in PWS patients is presumably explained by imprinting. The difference between AS and PWS suggests that simple
hemizygous deletion of UBG3A and GABRB3 does
not produce the epilepsy. The imprinting situation for
both genes is unclear. It is also possible that the
UBE3A and GABRB3 genes, located near each other,
may interact in some way.
In related studies, we have shown that GABRB3 expression, but not GABRB2 expression, is decreased at
autopsy in a brain of an AS child with the large common deleti~n.~’Homanics and co-workers28 inactivated the GABRB3 gene by gene targeting in embryonic stem cells and produced GABRB3-deficient mice.
These animals display frequent myoclonic and infrequent clonic-tonic seizures with EEG abnormalities,
similar to the epilepsy of AS.28,2‘ Furthermore, the
GABRB3-deficient mice are hyperactive, are hyperresponsive, show craniofacial abnormalities, and have
other phenotypic characteristics resembling AS29 (DeLorey TM et al, manuscript submitted). GABRB3,
therefore, remains a candidate gene to explain the severe epilepsy of AS.
Supported by NIH grants NS28772 (R.W.O.) and NS21908
(A.V.D.E.), as well as the Neurology and Research Services of the
West Los Angeles VA Medical Center, the Hospital for Sick Children in Toronto and the Bloorview Children’s Hospital Foundation, and the Angelman Syndrome Foundation, USA.
We thank Nancy Kilgaard, Charlotte McTerrell, Rohit Sharma, and
Amrita Hunjan for expert EEG technical support; Drs G. 0.
Walsh, A. Nyugen, H. Otsubo, M. Cortez, P. Hwang, and 0. C.
Snead 111 for helpful comments; Drs J. Wagstaff and M. Lalande for
referring class 111 and IV patients; and Drs P. Fang and A. Beaudet
for sharing their unpublished results. Elaine Modiest and Joan Spellman helped coordinate some patient studies. Special thanks to Ber-
nadettc Sakamoto, without whom none of this work would have
been possible.
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