RESEARCH ARTICLE

The Neurobehavioral and Molecular Phenotype of

Angelman Syndrome
Logan K. Wink,1* Sarah Fitzpatrick,1 Rebecca Shaffer,1 Sophia Melnyk,1 Amber H. Begtrup,1
Emma Fox,1 Tori L. Schaefer,1 Lauren Mathieu-Frasier,1 Balmiki Ray,2 Debomoy Lahiri,2
Paul A. Horn,1 and Craig A. Erickson1
1

Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio

Indiana University School of Medicine, Indianapolis, Indiana

Manuscript Received: 28 October 2014; Manuscript Accepted: 4 July 2015

Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment,
gait ataxia, and a unique behavioral profile. AS is caused by loss
of maternal expression of the paternally imprinted UBE3A gene.
In this study we aim to contribute to understanding of the
neurobehavioral phenotype of AS with particular focus on the
neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor
(BDNF) plasma levels in AS. Twelve individuals ages 3 years
or older with a confirmed genetic diagnosis of AS underwent
detailed medical history, phenotypic characterization, and
BDNF plasma sampling. The results of this study demonstrate
that individuals with AS suffer from significant developmental
delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary
behavioral domain noted in these individuals. The majority of
individuals in this project met criteria for autism spectrum
disorder on the Autism Diagnostic Observation Schedule
(ADOS); however, a negative correlation was noted between
ADOS score and developmental age. BDNF plasma levels in AS
individuals were significantly elevated compared to neurotypical
controls. This is the first report of abnormal BDNF levels in AS,
and one that necessitates larger future studies. The results
provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research.
2015 Wiley Periodicals, Inc.

Key words: angelman Syndrome; brain-derived neurotrophic

factor; BDNF

INTRODUCTION
Angelman Syndrome (AS) is a rare neurologic syndrome affecting
approximately one in 10,00025,000 children [ClaytonSmith,
1993; Petersen et al., 1995; Buckley et al., 1998; Mertz et al.,
2013] . AS is associated with severe developmental delay, speech
impairment, gait ataxia, and a unique behavioral profile. AS is
caused by loss of maternal expression of the paternally imprinted
UBE3A gene. The most common molecular cause of AS, occurring

2015 Wiley Periodicals, Inc.

How to Cite this Article:

Wink LK, Fitzpatrick S, Shaffer R, Melnyk
S, Begtrup AH, Fox E, Schaefer TL,
Mathieu-Frasier L, Ray B, Lahiri D, Horn
PA, Erickson CA. 2015. The
neurobehavioral and molecular phenotype
of Angelman syndrome.
Am J Med Genet Part A 167A:26232628.

in 7075% of individuals, is a maternally inherited deletion of the

AS critical region on 15q11-q13 [ClaytonSmith and Laan, 2009].
Mutations occurring in the maternal copy of the UBE3A gene,
paternal uniparental disomy (UPD) of chromosome 15, and
imprinting errors disrupting expression of UBE3A are additional
molecular defects that cause AS. In contrast to related developmental disorders such as autism, AS has a clear molecular basis.
Further characterization of the clinical phenotype of AS coupled
with investigation of the function of UBE3A could lead to a broader
understanding of mechanisms disrupted in a wide variety of
neurodevelopmental disorders. In this study we focus on the
neuropsychiatric presentation of AS and we report on plasma
brain-derived neurotrophic factor (BDNF) levels in AS patients.
We hypothesize that psychiatric symptoms including hyperactivity
and impulsivity will be common in individuals with AS and that
individuals with AS will have BDNF dysregulation.
Previous analyses of the genotype-phenotype correlation in AS
have demonstrated that individuals with AS have impaired cognitive and developmental functioning, relatively stronger cognitive
and receptive language skills than motor and expressive language
Conflict of interest: None.


Correspondence to:
Logan K. Wink MD, Cincinnati Childrens Hospital Medical Center,
3333 Burnet Ave. MLC 4002, Cincinnati, OH 4522.
E-mail: logan.wink@cchmc.org
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 29 July 2015
DOI 10.1002/ajmg.a.37254

2623

2624
skills, and individuals with deletion are more developmentally
delayed than the non-deletion individuals [Gentile et al., 2010].
Additionally, children with AS frequently have microcephaly,
mouthing behaviors, limited attention spans, ataxic gait, fascination with water, frequent laughter, and clinical seizures [Tan et al.,
2011]. Several phenotypic studies in AS have demonstrated
that a percentage of children with AS meet criteria for autism
spectrum disorder (ASD) when tested using currently accepted
diagnostic tools (Autism Diagnostic Observation Schedule
(ADOS) and Autism Diagnostic Interview Revised (ADI-R))
[Peters et al., 2004; Peters et al., 2012; Trillingsgaard and
Ostergaard, 2004]. The children with co-occurring autism in these
studies frequently scored lower on measures of cognitive functioning. Furthermore, the study by Trillingsgaard [2004] demonstrated
lower mental age correlated with higher ADOS scores amongst
participants.
Subsequently, there remains debate regarding the diagnosis of ASD
in children with AS, with several reports concluding that AS
children may receive the label of autism due to their severe level
of cognitive impairment and stereotypic mannerisms [Moss and
Howlin, 2009; Grafodatskaya et al., 2010; Williams, 2010].
Beyond the studies detailed above, to date there remains little
reported on the neuropsychiatric features of AS. Additionally, there
is a paucity of information describing the impact of UBE3A
disruption on human neurologic functioning as demonstrated
in AS. More generally in developmental disability studies, investigation of neurotrophins holds specific interest in linking molecular
changes to phenotypic presentation [Autry and Monteggia, 2012].
Neurotrophins regulate neural development, function, and
plasticity in vertebrate nervous systems and activate signaling
pathways which regulate cell survival, patterns of innervation,
dendritic pruning, and expression of proteins required for neuron
function [Huang and Reichardt, 2001]. BDNF, which is measurable in human plasma and known to cross the blood-brain barrier,
plays a critical role in neuronal development by supporting the
survival of existing neurons and the differentiation of new neurons
and synapses [Poduslo and Curran, 1996]. During development of
the central nervous system, BDNF acts as a signal for axonal
development required for growth of dopaminergic, GABAergic,
cholinergic, and serotonergic neurons [Autry et al., 2011]. In the
postnatal brain, BDNF modulates synaptic plasticity required for
learning and memory and contributes to structural plasticity of
dendritic spines, inducing changes in spine density and
morphology which help establish the neuronal network required
for learning and memory [Chapleau et al., 2009].
BDNF plasma levels are known to correlate with cerebral spinal
fluid levels in some psychiatric disease states and BDNF appears to
play an important role in modulating behavior, thus making BDNF
a biomarker of significant interest in investigation of neuronal
dysfunction caused by UBE3A deficiency [Autry et al., 2011; Haile
et al., 2014; Pillai et al., 2010]. However, no studies to date have
investigated BDNF regulation in humans with AS. In the AS mouse
model, work by Cao et al. [2013] demonstrated defective signaling
via the BDNF TrkB receptor resulting from elevated levels of
activity-related cytoskeletal-associated protein (Arc) due to disrupted expression of the Ube3a ubiquitin protein ligase [Cao et al.,
2013]. Furthermore, Peters et al. [2011] demonstrated changes in

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

diffusion tensor imaging parameters in multiple brain regions in
children with AS compared to controls, suggesting alterations
in myelination and axonal organization and decreased axonal
density or diameter that could be linked to aberrant BDNF
functioning [Peters et al., 2011].

METHODS
Twelve individuals age 3 years or older with a confirmed genetic
diagnosis of AS were recruited for this study. Recruitment occurred
via communication with the local AS community and advertisement with the Angelman Syndrome Foundation. The majority of
study participants were from the local community, however several
traveled from surrounding states. All subjects underwent detailed
medical history. Neurobehavioral characterization was undertaken
via completion of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), the Vineland Adaptive Behavior
Scales Interview Edition, 2nd Edition (VABS-II), the ADHD Rating
Scale, 4th edition (ADHDRS-IV), the Anxiety, Depression, and
Mood Scale (ADAMS), the Aberrant Behavior Checklist (ABC),
and the Childrens Sleep Habits Questionnaire (CSHQ). The
ADOS Module 1 and the ADI-R were completed to evaluate for
ASD. BSID-III, ADOS, and ADI-R were completed by clinicians
with expertise in AS. The remaining measures were administered
by a clinical research coordinator with extensive experience in
developmental disability research.
The BSID-III is a developmental assessment designed to measure cognitive, language, and motor functioning in children ages
142 months [Bayley, 2005]. Although this scale is not normed for
use in individuals above 42 months of age, it has been used
historically in AS research as an objective measure of cognitive
functioning [Gentile et al., 2010; Tan et al., 2011]. BSID-III scores
are reported as developmental age equivalents. The VABS-II has
been validated for individuals with intellectual disability up to the
age of 90 years and provides caregiver-reported information
regarding the individuals adaptive functioning in their home
environment [Sparrow et al., 2005]. Lower scores on the
VABS-II indicate lower functioning. The ADHDRS-IV is a
standardized assessment measure of ADHD symptoms, used
extensively in both ADHD and developmental disability literature
[DuPaul et al., 1998; Bohnstedt et al., 2005; Troost et al., 2006].
Higher scores on the ADHDRS-IV indicate more significant
symptoms, with scores ranging from 054. Raw scores were
used in this project, as percentile scores normed for the AS
population are not available. The ADAMS is a standardized
instrument designed to measure mood and anxiety symptoms
in individuals with developmental disability [Esbensen et al.,
2003]. Items on the ADAMS are rated on a scale of 0 to 3 (behavior
not a problem to behavior is a severe problem, respectively).
The ADAMS subscales analyze symptoms of mania, depression,
social avoidance, generalized anxiety, and obsessive/compulsive
behavior by caregiver report. Higher scores on each subscale
indicate more significant symptoms. The ABC is a caregiver-rated
questionnaire with demonstrated reliability and validity that has
been used in multiple studies of individuals with developmental
disabilities [Aman et al., 1985; Berry-Kravis et al., 2006]. Items on
the ABC are rated on a scale of 0 to 3 (behavior not a problem to

WINK ET AL.

2625

behavior is a severe problem, respectively). The ABC subscales

include irritability, social withdrawal, stereotypy, hyperactivity,
and inappropriate speech. Higher scores on each subscale indicate
more significant symptoms. The ABC inappropriate speech subscale is not reported due to severe speech impairment associated
with AS. The CSHQ is a tool designed to identify behavioral and
medically-based sleep problems in children ages 410 years, with a
score of 41 or greater indicative of need for referral to a sleep
specialist [Owens et al., 2000]. Although some of our study
participants fell outside of the normed age range for the CSHQ,
we believe this scale appropriately provides an overview of sleep
difficulties in our subjects.
The ADOS is a semi-structured assessment of social interaction designed to evaluate individuals with suspected ASD [Lord
et al., 1989]. Module 1 is intended for use in young children
with limited or no verbal speech. Due to the communication

deficits common to individuals of all ages with AS, Module 1 is

most appropriate for use in this disorder. However, it should be
noted that the ADOS is considered to be of limited value for
individuals with a mental age of 15 months and younger
[Gotham et al., 2007], and can be over-inclusive in classifying
individuals as having ASD when their primary deficit is intellectual or language disability [Luyster et al., 2009]. The total
communication and social cut-off score for ASD is 7, with
higher scores indicating a greater possibility of ASD or autism.
The ADI-R is a structured caregiver interview commonly used
in conjunction with the ADOS in determining presence of an
ASD and distinguishing ASD from other developmental disorders [Lord et al., 1994]. The ADI-R subscales are social,
nonverbal, and repetitive behaviors with cut-offs of 10, 7,
and 3, respectively. Higher scores on the ADI-R indicate
more significant ASD symptoms.

TABLE I. Mean Scores on Phenotypic Measures and Peripheral BDNF Levels

BSID-III cognitive subscale

VABS-II communication
subscale
VABS-II adaptive behavior
subscale
ADHDRS-IV
ADAMS manic/hyperactive
subscale
ADAMS depressed mood
subscale
ADAMS social avoidance
subscale
ADAMS generalized
anxiety subscale
ADAMS obsessive behavior
subscale
ABC Irritability Subscale
ABC lethargy subscale
ABC stereotypy subscale
ABC hyperactivity
subscale
CSHQ
ADOS
ADI-R social subscale
ADI-R nonverbal subscale
ADI-R repetitive behavior
subscale
BDNF

Total Group
18.7 months, SD 5.6 (n 11)
40.3, SD 14.7 (n 12)

Deletion
14.0 months, SD 5.9 (n 4)
34.3, SD 9.6 (n 4)

Non-deletion
21.4 months, SD 3.5 (n 7)
3.3, SD 16.4 (n 8)

Wilcoxon
P-values
P 0.04
P 0.62

42.4, SD 16.9 (n 12)

35.0, SD 13.1 (n 4)

46.1, SD 18.1 (n 8)

P 0.34

28.7, SD 9.0 (n 11)

9.2, SD 4.3 (n 11)

29.5, SD 8.8 (n 4)
8.0, SD 4.8 (n 4)

28.3, SD 9.7 (n 7)
9.9, SD 4.2 (n 7)

P 0.82
P 0.58

3.6, SD 5.3 (n 11)

4.8, SD 8.2 (n 4)

3.0, SD 3.6 (n 7)

P 0.93

5.0, SD 5.9 (n 11)

6.8, SD 8.2 (n 4)

4.0, SD 4.7 (n 7)

P 0.27

7.1, SD 7.0 (n 11)

5.8, SD 9.5 (n 4)

7.9, SD 5.8 (n 7)

P 0.61

2.7, SD 3.4 (n 11)

3.0, SD 5.1 (n 4)

2.6, SD 3.2 (n 7)

P1

17.9, SD 12.2 (n 11)

9.1, SD 10.2 (n 11)
7.3, SD 6.6 (n 11)
22.7, SD 12.0 (n 11)

11.8, SD 10.8 (n 4)
13.0, SD-15.7 (n 4)
9.0, SD 8.3 (n 4)
23.0, SD 16.0 (n 4)

21.4, SD 12.2 (n 7)
6.9, SD 6.0 (n 7)
6.3, SD 5.9 (n 7)
22.6, SD 10.6 (n 7)

P 0.29
P 0.49
P 0.68
P 0.89

55.7, (SD 4.2) (n 11)

8.9, SD 4.5 (n 12)
21.2, SD 4.1 (n 10)
11.8, SD 1.4 (n 10)
3.6, SD 2.9 (n 10)

53.8, SD 5.1 (n 4)
12.3, SD 5.5 (n 4)
21.6, SD 1.2 (n 3)
12.7, SD 1.2 (n 3)
2.6, SD 2.3 (n 3)

56.9, SD 3.4 (n 7)
7.3, SD 3.1 (n 8)
21.0, SD 2.9 (n 7)
11.4, SD 1.4 (n 7)
4.0, SD 3.2 (n 7)

P 0.18
P 0.14
P 0.88
P 0.41
P 0.63

3.7  103 pg/ml,

SD 2.3  103pg/ml
(n 11)

4.9  103 pg/ml,

SD 2.7  103 pg/ml
(n 4)

3.0  103pg/ml,
SD 2.2  103 pg/ml
(n 7)

P < 0.01

BSID-III: Bayley Scales of Infant and Toddler Development Third Edition.

VABS-II: Vineland Adaptive Behavior Scales Interview Edition 2nd Edition.
ADHDRS-IV: ADHD Rating Scale 4th edition.
ADAMS: Anxiety Depression, and Mood Scale.
ABC: Aberrant Behavior Checklist.
CSHQ: Childrens Sleep Habits Questionnaire.
ADOS: Autism Diagnostic Observation Schedule.
ADI-R: Autism Diagnostic Interview-Revised.
BDNF: Brain-derived neurotrophic factor.

2626
In addition to extensive phenotypic characterization, subjects
with AS and age-matched neurotypical control subjects had
peripheral blood collected for plasma BDNF assay. Neurotypical
controls were recruited from the community and evaluated via
clinician interview assessing developmental and psychiatric
history. One neurotypical control was age-matched (within 6
months) to each individual with AS. Approximately 4 ml of blood
was collected from both groups in EDTA-containing tubes. Within
30 min of collection, the blood was centrifuged at 1000g at 28 C
for 15 min. Plasma was collected and an additional centrifugation
of the collected plasma at 1000g at 28C for 10 min to completely
remove platelets from the samples. All plasma samples were stored
at 80C. To determine plasma BDNF level, a sensitive ELISAbased method was employed using a human BDNF ELISA kit from
R&D systems (Minneapolis, MN) that is validated for detection of
BDNF in human plasma [Grassi-Oliveira et al., 2008]. The amount
(pg/ml) of BDNF present in the plasma samples was determined
from the picogram value obtained in the standard curve using a
known amount of pure human BDNF, which was run at the same
time with subjects samples.
Prevalence of comorbid pathology was determined for the entire
AS study group, and for subgroups characterized as deletion
(n 4) versus non-deletion (n 8). The (exact) Wilcoxon rank
sum test was used to compare all measured variables between
deletion and non-deletion subjects (considered significant if
P < 0.05, no adjustment for multiple testing). The (exact)
Wilcoxon rank sum test was also performed to compare BDNF
plasma levels in AS participants versus controls (considered
significant if P < 0.05). Additionally, the Spearman correlation
coefficient was used to detect a possible association between
ADOS scores and Bayley developmental age. This project was
approved by our local Institutional Review Board.

RESULTS
Twelve individuals with a molecular diagnosis of AS participated in the
study; eight male and four female. Ages ranged from 3 to 29 with a mean
of 13.8 years (SD 8.0). All study participants were Caucasian. Four
participants had deletions, three had UPD, four had UBE3A mutations,
and one participant had an imprinting defect. One individual completed only ADOS, ADI-R, and VABS-II and was lost to follow-up
(female, UPD). Two participants did not complete the ADI-R (both
male, one UPD, one deletion). All results are reported in Table I.
All participants were significantly developmentally delayed. The
cognitive developmental age, as determined by the BSID-III Cognitive Subscale, ranged from 8 months to 25 months, with a mean
developmental age of 18.7 months (SD 5.6). Patients classified as
deletion scored lower than non-deletion subjects (P .04); this
was the only statistically significant difference found between
groups. The VABS-II scores also demonstrated communication
impairment (mean score 40.3 (SD 14.7)) and impaired adaptive
behavior (mean score 42.4 (SD 16.9)). ADHDRS-IV raw scores
demonstrated significant ADHD symptoms in the majority of
participants, with an ADHDRS-IV total mean score of 28.7
(SD 9.0). Scores on the ADAMS were most notable for elevation
in manic/hyperactive behavior with a mean score of 9.2 (SD 4.3)
on this subscale, however mean scores for the depressed mood,

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

social avoidance, generalized anxiety, and obsessive compulsive
behavior subscales were not elevated. Participants demonstrated
notable irritability captured by the ABC irritability subscale (total
mean score 17.9 (SD 12.2)). ABC lethargy and stereotypy
subscale scores were not elevated. The ABC hyperactive subscale
was elevated with a total mean score of 22.7 (SD 12.0). Scores on
the CSHQ demonstrated significant sleep impairment in nearly all
participants with total mean score of 55.7 (SD 4.2).
The ADOS total scores ranged from 3 to 15 (M 8.9, SD 4.5),
with 7 of 12 participants meeting the cut-off for ASD. The ADOS
scores correlated negatively with cognitive developmental age,
decreasing as cognitive developmental age increased (Spearman
correlation coefficient 0.86, P< 0.01). The ADI-R subscale
scores demonstrated significant social impairment in study
participants, with mean total social subscale score of 21.2 (SD
4.1), nonverbal subscale score of 11.8 (SD 1.4), and repetitive
behavior subscale score of 3.6 (SD 2.9). The means for all
subscales were above the diagnostic cutoffs of 10, 7, and 3,
respectively. Three subjects who scored below ASD cut-off on
the ADOS and also completed the ADI-R, all scored above the
ASD cut-off on the social and non-verbal subscales of the ADI-R.
Finally, BDNF plasma levels were found to be significantly
elevated in individuals with AS compared to neurotypical controls,
with a mean BDNF concentration of 3.7  103 pg/ml (SD 2.3
 103 pg/ml) in patients with AS versus 1.1  103 pg/ml (SD 2.3
103 pg/ml) in controls (P < 0.01) (Fig. 1).

DISCUSSION
The detailed neuropsychiatric phenotyping data gathered in this
study add to the growing body of phenotypic knowledge in AS
clinical research. Participants in this study suffered from
significant developmental delay and impaired adaptive
behavior. Hyperactivity was the primary behavioral symptom
present in study participants, as demonstrated by elevated
ADHD-RS, ABC hyperactivity, and ADAMS manic/hyperactivity scores. Additionally, the majority of study participants
demonstrated significant sleep disruption. Furthermore, the
majority of individuals in this project met criteria for ASD
on ADOS. However, the negative correlation between ADOS
scores and cognitive developmental age suggests that these
patients may have been misdiagnosed or over-diagnosed with
ASD by the ADOS due to their delayed cognitive development.
Our most striking finding is the significant elevation of plasma
BDNF in the AS participants compared to neurotypical controls.
This is the first report of abnormal BDNF levels in AS, and it
provides insight into potential molecular mechanisms of abnormal
neuronal development in this disorder. Elevated peripheral BDNF
levels may represent a direct consequence of deficient UBE3A
expression and present a target for future treatment development.
Interestingly, reduced levels of plasma BDNF have been demonstrated in depressed patients, with plasma BDNF levels normalizing
with successful antidepressant treatment, thus suggesting that
BDNF may be involved in supporting and elevating mood [Castren
and Rantamaki, 2010]. Intriguingly, our BDNF finding may offer
insight into the generally happy demeanor that has been part of the
characterization of AS since the initial description of the disorder.

WINK ET AL.

2627

FIG. 1. BDNF levels in controls vs.AS.

The findings from our report must be taken in the context of

several limitations of our study design. First, our sample size was
small, therefore it will be necessary to replicate both our phenotypic
and molecular findings within larger AS patient samples. While the
significantly elevated BDNF levels are intriguing, additional studies
should expand the analysis to include a matched control group
with idiopathic developmental disability. Another area for future
exploration is to compare BDNF plasma levels between AS and
individuals with chromosome 15q11-q13 duplication to assess
UBE3A dosage effect on peripheral BDNF levels. Finally, it will
be important to assess the relationship between peripheral and
central BDNF expression in pre-clinical models of AS in order to
provide additional validation of the importance of peripheral
BDNF in the neuropathophysiology of this disorder.

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