American Journal of Medical Genetics 132A:8 12 (2005)

Behavioral Aspects of Angelman Syndrome:

A Case Control Study
Raymond J. Berry,1 Robert P. Leitner,1* Adam R. Clarke,2 and Stuart L. Einfeld3
1

Angelman Syndrome Clinic, St. George Hospital, Kogarah, New South Wales, Australia
Departments of Psychology & Brain and Behaviour Research Institute, University of Wollongong, New South Wales, Australia
3
School of Psychiatry, University of New South Wales, Australia
2

Angelman syndrome (AS) is a rare congenital

disorder characterized by impairments in intellectual, neurological and motor functioning and a
postulated behavioral profile. This study compared behavioral characteristics of 62 individuals
with genetically confirmed AS and 29 individuals
with presumed AS from clinical features, with a
control group of young persons with intellectual
disability (ID) derived from an Australian epidemiological register. Twelve behavioral items from
the developmental behavior checklist (DBC) were
used for this comparison. The groups were matched for chronological age, gender, and level of ID. In
the AS group, significant differences were found
for 10 behaviors, with poor attention span and
impulsivity being less common, and overactivity/
restlessness, chewing or mouthing objects, eating
non-food items, gorging food, food fads, fascination for water, hand flapping and sleep disturbance being more common. Interestingly, there
was no difference in prevalence of unprovoked
laughter. Comparison of the results of the genetically confirmed with the genetically unconfirmed
AS cases showed no significant differences between individual behavior prevalence. These
findings show that a behavioral phenotype of
AS can be distinguished from others of similar
level of ID, but it is different from that hitherto
published. Abnormal food related behaviors, hyperactivity, fascination for water, hand flapping,
and sleep disturbance should be included in a
behavioral phenotype for AS. Apart from hyperactivity, ADHD-type behaviors are not more
characteristic of AS than in ID generally. Therefore, the Consensus Criteria for the diagnosis of
AS need to be reviewed. 2004 Wiley-Liss, Inc.

Abbreviations used: AS, Angelman syndrome; ABC, aberrant

behavior checklist; ADHD, attention deficit hyperactivity disorder; DBC, developmental behavior checklist; UBE3A, E6AP
ubiquitin protein ligase 3A; IM, imprinting mutation; ID,
intellectual disability; PWS, PraderWilli syndrome; UPD, uniparental disomy.
*Correspondence to: Dr. Robert P. Leitner, Director Angelman
Syndrome Clinic, Diagnostic and Assessment Unit, St. George
Hospital, Belgrave Street, Kogarah, NSW 2217, Australia.
E-mail: leitnerr@sesahs.nsw.gov.au
Received 6 October 2002; Accepted 19 February 2004
DOI 10.1002/ajmg.a.30154

2004 Wiley-Liss, Inc.

KEY WORDS:

Angelman syndrome; case-control study; behavior; behavioral

phenotype; developmental behavior checklist

INTRODUCTION
Angelman syndrome (AS) was first described in 1965
[Angelman, 1965]. The current estimated incidence of AS is
between 1 in 10,000 and 1 in 20,000 births and over 450 cases
have been reported [Clayton-Smith, 1992; Laan et al., 1999].
The diagnosis of AS is based on a combination of the clinical
features listed in the Consensus Criteria for the Diagnosis of
AS [Table I, Williams et al., 1995b] and genetic laboratory
testing [Williams et al., 2003]. The Consensus Criteria
Behaviors reported as features of individuals with AS are
shown in Table II. AS is associated with abnormalities of
maternal chromosome 15q11-13, and in Australia, the diagnosis of AS can be confirmed by available genetic testing in
about 80% of cases [molecular classes I, II, IIIJiang et al.,
1999]. Familial recurrence risk can be as high as 50% in
families of individuals with inherited IM mutation, who
demonstrate a detectable deletion of the imprinting center
(
50% of this group); in those with inherited UBE3A mutation;
and in those with no molecular genetic abnormality (molecular
classes IIIa, IV, and V respectively). Otherwise, familial
recurrence is rare [Jiang et al., 1999; Williams et al., 2003].
A behavioral phenotype is best described as the heightened
probability or likelihood that individuals with a given
syndrome will exhibit certain behavioral and developmental
features relative to those without the syndrome [Dykens,
1995]. Studies attempting to define behavioral phenotypes
should seek to: (1) obtain evidence of an association by means of
a case-control study, (2) rule out chance with tests of statistical
significance and corrections for multiple comparisons, (3)
consider a type 2 error where no association is found, (4)
measure or control for confounding variables, (5) reduce
ascertainment bias with attention to selection, and (6) reduce
and evaluate measurement error by using measures of known
reliability and validity [Einfeld and Hall, 1994]. Most literature reports of behavior in AS have been descriptive,
uncontrolled studies without comparison to matched control
groups; they therefore fail to define adequately a behavioral
phenotype for AS [Robb et al., 1989; Fryburg et al., 1991; Zori
et al., 1992; Clayton-Smith and Pembrey, 1992; ClaytonSmith, 1993; Jolleff and Ryan, 1993; Penner et al., 1993;
Bottani et al., 1994; Saitoh et al., 1994; Buntinx et al., 1995;
Summers et al., 1995; Williams et al., 1995a; Burger et al.,
1996; Laan et al., 1996, 1998, 1999a,b; Smith et al., 1996, 1997,
1998; Buckley et al., 1998; Moncla et al., 1999a,b; Oliver et al.,
2002].

Behavioral Aspects of Angelman Syndrome

TABLE I. Angelman Syndrome: Clinical Characteristics [Williams et al., 1995b]

A: Consistent (present in 100%)
Developmental delay (functionally severe)
Speech impairment (none or minimal use of words, better receptive, and non-verbal skills)
Movement and/or balance disorder (usually ataxia of gait and/or tremulousness of limbs)
Behavioral uniqueness (any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable, often with hand
flapping; hypermotoric behavior; short attention span)
B: Frequent (present in more than 80%)
Absolute or relative microcephaly by age 2
Seizures, onset usually <3 years
Abnormal EEG; large amplitude slow-spike waves (23 Hz), usually facilitated by eye closure
C: Associated (present in 2080%)
Flat occiput/occipital groove
Protruding tongue/tongue thrusting
Suck/swallow disorders, feeding problems during infancy
Prognathia/wide mouth and widely spaced teeth
Frequent drooling/excessive chewing/mouthing behaviors
Strabismus
Hypopigmented skin, light hair and eye color, seen only in deletion cases
Hyperactive lower limb deep tendon reflexes
Uplifted, flexed arm position especially during ambulation
Increased sensitivity to heat
Sleep disturbance
Attraction to/fascination with water

Only two studies have attempted to define a behavioral

phenotype in AS in a case-control manner [Summers and
Feldman, 1999; Clarke and Marston, 2000]. Carers in both
studies completed the aberrant behavior checklist (ABC), a
58-item standardized rating scale of maladaptive behavior in
developmental disability [Aman et al., 1985a,b, 1995; Bihm
and Poindexter, 1991; Rojahn and Helsel, 1991; Marshburn
and Aman, 1992]. Summers and Feldman [1999] found that 27
individuals with AS (deletion, UPD, methylation positive but
genetic mechanism unknown, and clinical diagnosis only)
had lower scores in irritability/agitation and lethargy/withdrawal subscales than two control groups [Summers and
Feldman, 1999]. Clarke and Marston [2000] found that 72
individuals with AS caused by deletion had less prominent
behaviors related to lethargy/withdrawal and inappropriate
speech, and had more prominent behaviors related to hyperactivity/non-compliance than two control groups. Hyperactivity was negatively correlated with advancing age [Clarke and
Marston, 2000]. The findings in both studies support the
observations of happy and sociable demeanor in individuals

with AS, and that hyperactivity is relatively more common in

AS than in intellectual disability (ID) of unknown genetic
etiologies. One study, which examined the prevalence of AS in
Sweden, suggested that AS has a high prevalence of Autism
(Table II) not explained by the coexisting severe ID and
epilepsy [Steffenberg et al., 1996], but this has not been
corroborated by the recent case-control studies.
Better definition of the behavioral phenotype would have
potential importance in AS. Firstly, an accurate behavioral
phenotype would assist early clinical diagnosis of AS. The
benefits of early diagnosis include institution of early interventions (such as behavior modification), planning of treatment, and provision of prognostic information [Hersh et al.,
1981, Summers et al., 1995, Summers and Feldman, 1999;
Clarke and Marston, 2000]. Earlier genetic counseling could be
offered to families of individuals with AS with inherited defects
of molecular classes III, IV, and V, to assist parents in making
informed decisions regarding the substantial potential risk (as
high as 50%) of recurrence in future pregnancies, possibly
preventing conception of further affected individuals [Kishino
et al., 1997; Matsuura et al., 1997; Jiang et al., 1999].
The aims of this study were:

TABLE II. Prevalence of Behaviors in AS in the Literature

Consistent behaviors100%
Laughter/smiling
Happy demeanor
Excitable personality/hand flapping
Hyperactivity/hypermotoric activity
Short attention span
Associated behaviors: 2080%
Tongue thrusting
Drooling
Chewing, licking, mouthing objects
Attraction to/fascination with water
Sleep disturbance
Increased heat sensitivity
Other behaviors
Feeding problems in infancy
Fixation on food, food fads
Overeating/hyperphagia associated with obesity
Autism

Prevalence

42100%
88100%
84%
5094%
Most

Most
7576%
7585%
68%
5790%
Uncertain
4487%
33100%
750%
100%

*
*

To calculate the prevalence of 12 behaviors characteristic of

AS in our cohort of individuals with AS and to compare these
with the findings in descriptive AS studies,
To compare our findings with those of previous case-control
studies [Summers and Feldman, 1999; Clarke and Marston,
2000],
To determine if these behaviors were more characteristic of
individuals with AS than individuals with ID without a
genetic diagnosis, thereby better defining a behavioral
phenotype in AS,
To analyze behaviors in our study commonly reported in AS
which had not been addressed by these studies,
To determine if there were any differences in behavioral
profiles between genetic subtypes of AS.

MATERIALS AND METHODS

The study subjects were drawn from an Angelman syndrome
Clinic in Sydney, which is closely linked to the Angelman

10

Berry et al.

syndrome Association of Australia. The clinic has records of

over 98 individuals diagnosed according to Consensus Criteria
for the Diagnosis of AS [Williams et al., 1995b], 24 of whom
have been reported previously [Leitner and Smith, 1996]. We
collected behavior data on 91 individuals. The 62 individuals
(35 male, 27 female) who had genetic confirmation were our
primary AS study group. The mean age of the AS study group at
questionnaire completion was 13.6 years (range: 1.340.7
years). The diagnosis was confirmed by cytogenetic or
molecular DNA studies in all individuals. Forty-four individuals (71%) had a maternal 15q11-13 deletion, 11 (18%) had
UPD, 4 (6%) had IM, and 3 (5%) had an abnormal methylation
result but unknown mechanism. Imprinting center deletion
and UBE3A mutation analysis were not performed (not
available in Australia). The 29 individuals (11 male, 18 female;
mean age at questionnaire completion 11.8 years (range: 1.7
31.5 years)) with incomplete genetic confirmation were
analyzed separately. Sixteen individuals had a normal methylation test, and 13 had negative deletion and UPD testing, but
had not had IM testing. All individuals with AS had moderate
to profound ID. The intellectual levels were obtained from the
results of psychometric assessments, reports in the patients
medical records, or the Angelman syndrome questionnaire.
Control subjects were taken from an epidemiological register
of children and adolescents with ID forming part of the
Australian Child to Adult Development Study [Einfeld and
Tonge, 1996a,b]. There were 340 control participants with
moderate to profound ID in this study. Intellectual levels were
mostly obtained from Department of Education records of IQ
tests, and some were obtained through IQ tests obtained as
part of the study.
As part of the normal case management procedure, carers
complete a comprehensive Angelman syndrome questionnaire,
which requests information on all aspects of the individuals
problems, including behavior. Twelve items on behavior from
the developmental behavior checklist (DBC) were chosen to be
included in the questionnaire, which are specific behaviors
that are part of the Consensus Diagnostic Criteria for AS
[Williams et al., 1995b] that were identified by carers of AS
individuals as prominent problems. These were broadly
grouped into: ADHD type behaviors (items 9, 19, 37, 50);
food-related behaviors (items 10, 21, 26, 27); and other
behaviors (items 42, 44, 60, 67-Table III). The DBC is a 96item questionnaire, which assesses behavior and emotional

disturbance in young people with ID. It has robust reliability

and validity characteristics [Einfeld and Tonge, 1992, 1995,
1996a,b]. The questionnaires were completed between May
1995 and May 2000.
Data Analysis
In the first part of the analysis, differences in rates of
behavior were compared between the AS and control groups
using Chi square analysis. A modified Bonferroni procedure
was employed to correct for multiple comparisons to maintain
the family wise error rate for each set of analyses at a 0.05
[Keppel, 1982]. Thus, with 12 planned comparisons, the
significant results for the questions were confirmed at the
a 0.0041 level or below. In the second part of the analysis,
rates of reported behavior were compared between the deletion
and UPD groups. Data from the IM group was excluded from
this analysis due to the small number of subjects with this
genetic mechanism. Differences in rates of behavior were also
compared between the genetically confirmed and unconfirmed
subjects using Chi square analysis.
RESULTS
The individual prevalence rates of the 12 DBC items in our
group of AS individuals, their prevalence in the available
literature and the comparison between the behaviors in the AS
and ID groups are shown in Table III. The study and control
groups were well matched, with no significant group differences found for age, gender, or level of ID.
Of the 12 DBC items examined, two items (poor attention
span and impulsivity) were significantly less common in the AS
group. Eight items (hyperactivity, chewing or mouthing
objects, eating non-food items, food fads, gorging food, fascination with water, hand flapping, and sleep disturbance) were
significantly more common in the AS group. There was no
difference in the prevalence of unprovoked laughter and
distractibility between the study group and controls.
No significant group differences were found for the rates of
reported behaviors between the deletion and UPD subgroups of
individuals with AS. When the study group of 62 genetically
confirmed individuals with AS was compared with the group of
29 individuals with a presumed but genetically unconfirmed
diagnosis of AS, there were no significant differences in
prevalence for any behavior between the two groups.

TABLE III. Comparison of Percentage Reported Rates of Behaviors in AS (Literature and Study Groups) and Controls
Percentage of subjects exhibiting behavior (%)
DBC question
9: Cannot attend to one activity for any length of time, poor attention spanb
19: Easily distracted from his/her task, e.g., by noisesb
37: Impulsive, acts before thinkingb
50: Overactive, restless, unable to sit stillb
10: Chews or mouths objects, or body parts
21: Eats non-food items, e.g., dirt, grass, soap
26: Fussy eater or has food fads
27: Gorges food, Will do anything to get food, e.g., takes food out of garbage bins or
steals food
42: Laughs or giggles for no obvious reason (bursts of laughter)
44: Likes to hold or play with an unusual object, e.g., string, twigs (fascination for
water)
60: Repeated movements of hands, body, head or face, e.g., hand flapping or rockingb
67: Sleeps too little, disrupted (disturbed) sleep
a

Significant group difference.

Items common to DBC and ABC.

AS literature

AS study
group (n 62)

Controls
(n 340)

Most
Most

5094
7585
82
33100
750

45.8a
81.4
27.1a
71.2a
76.3a
42.4a
69.5a
33.9a

73.8
76.2
60.3
49.3
43.4
19.3
38.8
16.2

42100
68

49.2
71.2a

49.6
34.5

84
5790

67.8a
67.8a

37.1
26.4

Behavioral Aspects of Angelman Syndrome

DISCUSSION
The results of our study confirm that the AS group had
similar behavioral profiles to those previously recorded in
the AS literature. We recorded previously undocumented
prevalence rates for impulsivity and eating non-food items
in AS. Because the ABC used in previous case-control
studies analyzed only 5 of the 12 behaviors we selected
[Aman et al., 1985a,b], this study produced new case-control
data on 7 behaviors. These behaviors are: the four foodrelated behaviors (chewing/mouthing objects, eating non-food
items, food fads, gorging food/increased appetite), unprovoked
laughing, fascination for water and sleep disturbance (see
Table III).
The prevalence figures in this study demonstrate that a
behavioral phenotype for AS is different and probably
distinguishable from non-AS individuals with similar levels
of ID. Of the ADHD-type behaviors, hyperactivity is more
common and poor attention span and impulsivity are less
common, and all are discriminating behaviors in individuals
with genetically confirmed AS. Distractibility is not discriminatory. Therefore, the inclusion of short attention span in the
Behavioral Uniqueness category of Consensus Diagnostic
Criteria [Williams et al., 1995b] is inaccurate.
All four food-related behaviors are significantly more
characteristic of the AS group. Because they are discriminatory in our AS group and they have not been analyzed closely
before, these behaviors in particular add to existing knowledge
of the behavioral phenotype of AS. The behavior of gorging
food/increased appetite in our AS group correlates with clinical
overlap between AS and PWS already described [Kirkilionis
et al., 1991]. The other behaviors of fascination for water,
hand flapping, and sleep disturbance are more characteristic of
AS. Surprisingly, unprovoked laughter, a behavior regarded as
a pathognomonic feature of AS in virtually all descriptive
studies, is not more characteristic of AS in our study. There
were no significant differences in behavior rates between the
deletion and UPD subgroups of AS in our study. This raises the
possibility of a consistent behavioral phenotype in AS in the
presence of a variable genotype and physical phenotype [Lossie
et al., 2001].
There are a number of possible limitations in this study. Only
12 items from the DBC were used to evaluate behavior in AS.
Although these behaviors were derived from the list of
consensus diagnostic criteria [Williams et al., 1995b] a more
complete picture of the behavioral phenotype in AS, would
have been obtained if the complete DBC (96 items) was used.
The question of autism being present in AS [Steffenberg et al.,
1996] is not addressed by this study. The DBC contains items
that are autism relating behaviors, but these were not
included in the items we selected, so analysis for autism-type
behaviors was not possible. The numbers of individuals in the
UPD and IM groups were small, preventing us from drawing
any firm conclusions from our finding of a consistent
behavioral phenotype across genetic subtypes. More accurate
comparison of the behavioral profiles of genetic subtypes of AS
could have been achieved by performing a complete DBC
analysis. The authors are currently in the process of administering the complete 96-item DBC to our group of AS
individuals to address these points.
The AS group was not controlled for the possible confounding
effect of anticonvulsant (80% of the group) or other medications. However, in the study by Summers and Feldman [1999],
medication was not a significant factor in the analyses.
Ascertainment bias is possible because AS individuals were
recruited through a specialist clinic. Reliance on career
questionnaire responses to establish the level of intellectual
functioning for some of the individuals with AS is another
potential weakness. Interpretation of behavior may vary

11

between observers, but the DBC has been shown to have good
inter-observer reliability.
In conclusion, we believe this study has contributed to
defining a behavioral phenotype in AS. Hyperactivity, all four
food-related behaviors, fascination for water, hand flapping,
and disturbed sleep are characteristic behaviors in AS and
should be part of its behavioral phenotype. The ADHD-type
behaviors of poor attention span, impulsivity and distractibility, previously thought to be characteristic of AS, were not
discriminating behaviors, and poor attention span should be
removed from the consensus diagnostic criteria for AS. This
study casts some doubt on whether unprovoked laughter is
characteristic of AS, a feature consistently described since
the syndrome was first reported and regarded as virtually
pathognomonic of AS. Eating behaviors found to be characteristic of AS in our study are very similar to those characteristic
of PWS, indicating some behavioral overlap between these
syndromes. Further case-control studies should be carried out
to confirm that unprovoked laughter is not characteristic of AS
and that eating behaviors in AS and PWS are very similar.
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