Angelman Syndrome:

Identification and Management

Daniela Bonello
Francesca Camilleri
Jean Calleja-Agius, MD, MRCOG, MRCPI, MSc, PhD

Continuing
Nursing Education
(CNE) Credit
Abstract
Attention Readers: The
Angelman syndrome (AS) is a neurobehavioral and genetically determined condition, which affects
test questions are provided in this approximately 1 in 15,000 individuals. It is caused by various genetic mutations and deletions of the
issue, but the posttest and evaluation maternally-inherited UBE3A gene, on the 15q11-13 chromosomal region. The UBE3A gene, which encodes
must be completed online. Details to
complete the activity are provided E3 ubiquitin ligase, shows tissue-specific imprinting, being expressed entirely from the maternal allele.
online at academyonline.org/CNE. The diagnosis of AS is confirmed either by methylation test or by mutation analysis. A more severe
A total of 3 contact hour(s) may be clinical picture is linked with the deletion phenotype.
earned as CNE credit for reading
this article, “Beckwith-Wiedemann Patients with AS have a behavioral and motor pattern defined as “happy puppet” because it is
Syndrome Review: A Guide for the characterized by puppet-like ataxic jerky movements; a happy, sociable disposition; and paroxysms of laughter.
Neonatal Nurse,” and “Prader-
Willi Syndrome: Background and
There is currently no cure for AS, and management is mainly symptomatic. Novel therapeutic
Management,” and completing the options are directed toward the possibility of activating the silenced paternal copy of the UBE3A gene.
online posttest and evaluation. To be
successful the learner must obtain a
grade of at least 80% on the test. Test Keywords: UBE3A gene; seizures; genomic imprinting; GABA; ataxia; ubiquitin pathway
expires three (3) years from publication
date. Disclosure: The author/planning
committee has no relevant financial
interest or affiliations with any

commercial interests related to the
subjects discussed within this article. No
commercial support or sponsorship was
provided for this educational activity.
ANN/ANCC does not endorse any
commercial products discussed/
displayed in conjunction with this
educational activity.
The Academy of Neonatal Nursing is
accredited as a provider of continuing
nursing education by the American
Nurses Credentialing Center ’s
Commission on Accreditation.
Provider, Academy of Neonatal
Nursing, approved by the California
B oard of R egis tered Nursing,
Provider #CEP 6261; and Florida
Board of Nursing, Provider #FBN
3218, content code 2505.
The purpose of this article is to provide
neonatal health care professionals
with information regarding the
pathophysiology, identification, and
treatment of Angelman syndrome.
Accepted for publication
December 2016.
A
ngelm a n s y n drom e (A S) w a s 
 originally described in 1965 by a
British pediatrician, Dr. Harry Angelman. He
reported the clinical findings in three severely
mentally-retarded children, who had learning
disability, inability to speak, ataxic and jerky
movements, and easily provoked laughter.1,2
Initially, no known cause could be found
responsible for AS; however, in 1987, a dele-
tion of chromosome 15q11-13 was identified
in two patients by Magenis and colleagues.
Subsequently, it was shown that AS can be
caused by various genetic mechanisms involv-
ing this imprinted region of the genome.1,3
EPIDEMIOLOGY
Very often, the incidence of AS is quoted
to be between 1 in 15,000 and 1 in 20,000.
However, the number of cases may be under-
reported because of misdiagnosis or underes-
timation of signs that can be subtle, especially
in early life.4
Lifespan in AS patients appears to be
nearly normal. However, longevity in AS may
be possibly reduced as a result of risk factors
such as seizures. Nevertheless, there is some
conflicting evidence in the literature and so
no definitive conclusions can be made.2,5
Pathophysiology and Genetics
The many characteristic features of AS are
caused mainly by the combination of a dysfunc-
tion of the maternal allele of the UBE3A gene
and paternal imprinting. The UBE3A gene is
located on the long (q) arm of chromosome
15 between Positions 11 and 13 (15q11-q13).
The enzyme encoded by this gene is
mainly involved in the ubiquitin-proteasome
pathway which is extremely important to all
cells, especially brain neurons. This pathway
involves the degradation of selected proteins
and is part of the constant protein turnover
that occurs in cells.5
Normally, two copies of the UBE3A gene
are inherited, one from the mother and one

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 from the father. In certain areas of the brain, the paternal
copy of the gene is inactivated by the normal process of
genomic imprinting, and as a result, only one working copy
of the gene is inherited.6
A mutation in the remaining active maternally derived
gene prevents the formation of the enzyme in the brain. The
loss of enzyme function is therefore the underlying molecular
mechanism responsible for most cases of AS and the most
likely cause of the features observed in AS.5
In the sister syndrome, Prader-Willi Syndrome (PWS),
imprinting occurs on the maternally derived allele of the
same locus (15q11-q13), and mutations on the paternal allele
are responsible for the manifestation of PWS.5
There are four different mutational mechanisms known
to cause AS, all of which affect and interfere with maternal
UBE3A gene expression at the 15q11-13 locus.7 As shown
in Table 1, patients are grouped into five classes according to
the pathophysiology of the syndrome.5
When compared with the other classes, Class I patients
with a chromosomal deletion present the worst clinical phe-
notype (e.g., motor difficulties, microcephaly, seizures, and
speech impairment).2 Approximately 70 percent of patients
have a de novo deletion on the 15q11-13 maternal chromo-
some. These deletions have common breakpoints and are
of similar size of approximately 4 megabases (Mb). A few
patients have similar but slightly different deletions arising de
novo or as unbalanced translocations.8
Individuals suffering from AS may exhibit different
signs and symptoms of different severity. This is because
of variable expressivity and penetrance, where the same
mutation is not always expressed to the same extent in the
individuals who carry it. Some examples of phenotype vari-
ability resulting from variance in gene structure include:
(1) loss of the HERC2 gene transcript during the deletion
is responsible for blue eyes in many AS patients; and (2)
the deletion of the OCA2 gene, whose protein determines
the pigmentation of the skin, eyes, and hair and which is
also located on the chromosome 15, is responsible for the
light-colored hair and fair skin observed in AS patients.
Phenotype variability may make the diagnosis of AS more
challenging. 5
TABLE 1  ■  The Different Classes of Genetic Mechanisms Leading to
Angelman Syndrome5
Class Genetic Mechanism Frequency (%)
I Deletion 70–75
II Uniparental disomy 2–3
III Imprinting defect 3–5
IV UBE3A mutation 5–10
V Unknown 10–15
Other chromosome rearrangements 1–2
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Neurophysiology of Angelman Syndrome
There is evidence that the neurologic deficits observed in
AS patients may result from specific abnormalities in synaptic
development and plasticity.9 Experiments carried out on AS
mice models have shown that UBE3A is required for cortical
plasticity and experience-driven plasticity. The experiments
show reduced dendritic spine density and length which may
be relevant to the cognitive deficits and motor impairment.10
Mice models have also demonstrated deficits in hippocampal
long-term potentiation (LTP) and deficits in hippocampus-
dependent memory that likely explains the learning and
memory impairment in patients with AS.11
Signs and Symptoms
The characteristic signs and symptoms of AS evolve slowly
with age. Initially, there is overlap with features of other dis-
orders, some of which are listed in Table 2. As a result of this,
most AS cases are not diagnosed during early infancy because
the developmental problems are still very nonspecific during
this period.2,4,5,12
Developmental and physical characteristics have been
described to establish clinical criteria for the diagnosis of
AS syndrome, as shown in Table 3. 5 However, these clin-
ical criteria are not absolute proof of diagnosis and ulti-
mately the condition should always be confirmed by genetic
testing.12
As soon as a baby is born, neonatal nurses should be
attuned to specif ic physical/dysmorphic features. This
requires knowledge not only of AS but of other genetic con-
ditions. A full neurologic exam should be carried out and
nurses should especially observe for hypotonia, and sucking
and swallowing difficulties. The neonate may have difficulty
in establishing breastfeeding. These problems account for
the most frequent reasons for NICU admissions of these
babies. Nonetheless, such features, especially if mild, can also
be observed in normal infants or in those presenting with
other conditions. Moreover, the more characteristic fea-
tures of AS present later on in childhood and therefore early
investigations, such as genetic studies are not warranted.13
The role of neonatal nurses may extend beyond this period,
into the long-term management of such patients. Adequate
training, as well as up-to-date courses and programs, should
be regularly offered to neonatal nurses.14
The phenotypic characteristics listed in Table 3 may vary
from one patient to another. Many patients have normal pig-
mentation, whereas others have a normal head circumference.
Seizures may be absent in some cases, and in others, some
degree of speech may be present. Moreover, the characteristic
dysmorphic face may not be present in certain patients, who
would also have minimal ataxia.1
The most consistent and striking clinical features are the
behavioral ones, and for this reason, these are the characteristics
that usually prompt clinicians to consider the diagnosis of AS.1
The physical and behavioral features that are manifested
in AS evolve in relation to the age of the patient. Most of the
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 TABLE 2  ■  A List of Possible Differential Diagnoses for Angelman Syndrome2,4,5,12

Similar Features to Angelman Syndrome Specific Features of Angelman Syndrome

Rett syndrome Absent speech Almost exclusively affects females

Microcephaly Mutation in the gene MECP2
Stereotypical hand movements Hyperventilation
Poorly controlled seizures Hand-flapping movements
Periodic breath spells
Small and cold hands
Mowat-Wilson syndrome Severe mental retardation Heterozygous deletion/truncating mutations in
Seizures the gene ZFHX1B
Microcephaly Agenesis of corpus callosum
Short stature Congenital heart defect
Uplifted ear lobes
Constipation
Pitt-Hopkins syndrome Intellectual disability Coarse facial features with prominent lips
Developmental delay (psychomotor) Agenesis of corpus callosum
Seizures Hyperventilation
Happy, excitable demeanor
Microcephaly
X-linked alpha-thalassemia/mental Severe mental retardation Mutations in the gene XPN
retardation syndrome (ATRX) Seizures X-linked, therefore affects boys
Absent speech development Severe hypotonia in infancy
Genital abnormalities
Anteverted nares
Tented upper lip
SLC9A6 associated X-linked disorder Mental retardation Fast EEG rhythm
Microcephaly Dystonia
Absent speech
Abbreviation: EEG 5 electroencephalogram.

clinical features mentioned in Table 3 become more evident
and clear from the age of 1 year.1 Children with AS experi-
ence puberty at the expected age, and they develop normal
secondary sexual characteristics.1
Adult A S patients show pronounced mandibular
prognathism, pointed chin, macrostomia, and prominent
lower lip.1,2 Moreover, in some, eyes may become more
deeply set.1 However, other features, such as ataxia, become
less striking as the patients develop reduced mobility because
of limb hypertonicity and thoracic scoliosis.1,2
Even though in late childhood and adolescence the fre-
quency of seizures may decrease, most adults still experience
seizures mainly myoclonic and atypical absence seizures.1,2
With progression into adulthood, the behavior changes as
well. Hyperactivity is reduced, attention span increases,
and sleeping problems improve. 2 Certain adult patients
may exhibit an aggressive behavior and frustration espe-
cially when finding it difficult to communicate.1 In fact, in
most AS patients, speech does not develop, and therefore,
communication difficulties are a prominent feature of this
syndrome. Patients may have a vocabulary of two or three
words only.1
As a result of severe mental retardation and delayed devel-
opmental milestones, children with AS fail to acquire motor,
cognitive, and language skills. Although social development
may also lag behind, children with AS do acquire some social
skills and manage to fit in well with other children.1,15
Because of delayed motor development, muscle tone in AS
patients is abnormal. They show truncal hypotonia because
of weak and inflexible muscles of the trunk and also hyperto-
nicity of the limbs and brisk reflexes.1
Seizures and abnormal electroencephalogram (EEG)
patterns are characteristic signs of AS which lead to an early
diagnosis. Most patients present with epileptic seizures
during the first three years of life.4
In childhood, all types of seizures have been described,
ranging from jerky movements of all extremities to brief
periods of lack of awareness. However, the types of seizures
typical of AS are atypical absences, myoclonic seizures, and
nonconvulsive status epilepticus (NCSE). Atypical absences
are considered as staring spells which may be difficult to dis-
tinguish from the usual behavior of an individual. Myoclonic
seizures are brief jerks of a single muscle or a group of
muscles, whereas NCSE lead to more subtle epileptic activity,

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 TABLE 3  ■  Main Clinical Diagnostic Criteria for Angelman Syndrome

Consistent (100%) Frequent (.80%) Associated (20% –80%)

Severe developmental delay A delayed and disproportionate growth Flat occiput

Speech impairment with no or minimal
use of words; nonverbal and receptive
communication skills are higher than
verbal ones
Movement disorder, usually ataxic and/or
tremulous movement of the limbs
Unique behavioral features: a combination
of frequent and inappropriate laughter,
easily excitable personality, often with
hand flapping movements and short
attention span
in head circumference, leading to
microcephaly by the age of two years;
this being more pronounced in those with
15q11.2-q13 deletions
Onset of seizures, usually ,3 years of age
A characteristic EEG pattern with large
amplitude slow spike waves and triphasic
waves
Protruding tongue
Tongue thrusting; suck/swallowing disorders
Feeding problems during infancy
Truncal hypotonia
Prognathia
Wide mouth, widely spaced teeth
Frequent drooling
Excessive chewing/mouthing behaviors
Strabismus
Hypopigmented—light skin, hair, and eye color
compared with the family (seen only in deletion
cases)
Hyperactive lower extremity deep tendon reflexes
Wide-based gait with pronated or valgus-positioned
ankles
Uplifted, flexed arm position especially during walking
Increased sensitivity to heat
Sleep disturbances
Attraction to/fascination with water
Abnormal food-related behaviors
Obesity (in childhood)
Scoliosis
Constipation

Abbreviation: EEG 5 electroencephalogram.

Adapted from Van Buggenhout G, Fryns JP. Angelman syndrome (AS, MIM 105830). Eur J Hum Genet. 17;2009:1367-1373; Clayton-Smith J, Laan L.
Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet. 2003;40:87-95; Williams CA. Angelman syndrome: Consensus
for diagnostic criteria. Am J Med Genet. 1995;56:237-238.

when the individuals do not appear as their “usual selves.”12
Although the pathogenesis of epilepsy in AS is not fully
understood, GABAergic dysfunction has been hypothesized
to contribute to the presence of epilepsy and neurotransmis-
sion impairment in many patients with AS.4
Specific EEG anomalies are observed in AS patients,
which, together with epileptic crises, help early diagno-
sis of AS. Three typical patterns are mainly observed in
very early infancy, namely, persistent generalized rhythmic
4–6 Hz activity reaching more than 200 mV of amplitude,
not associated with drowsiness, prolonged rhythmic delta
(triphasic) activity of 2–3 Hz with a moderate amplitude
of 200–500 mV, more evident over the frontal regions and
mixed with spikes or sharp waves; and spikes and sharp waves
mixed with 3–4 Hz components, usually with amplitude of
more than 200 mV, are mainly seen posteriorly and are facili-
tated by or only seen on eye closure.1,4
DIAGNOSIS
The diagnosis of AS is based on clinical, behavioral, and
developmental phenotypes, as well as laboratory genetic
tests. 2 An AS is diff icult to diagnose because the signs
and symptoms evolve with age and overlap with those of
other disorders. 2 The characteristic features are shown in
Figure 1.
Behavioral characteristics such as a happy demeanor, par-
oxysmal laughter, sleeping problems, and hyperactivity are
quite striking in these patients, and they are the first features
to be analyzed by clinicians in their diagnosis.2 Early diagno-
sis is important for early therapeutic intervention especially of
epileptic seizures and for genetic counseling.18
It has been suggested that to make a good diagnosis, the
observable traits of AS should be assessed using measurable
criteria in at least five domains: intellectual function, lan-
guage and speech, attention span, social impairments, and
other behavioral disturbances.5
Diagnostic Tests
The clinical diagnosis of AS is confirmed by laboratory
testing with the two main approaches being the cytogenetic
approach and molecular testing. The EEG findings can also
help in the diagnosis of AS.
The cytogenetic approach involves routine analysis of chro-
mosomes by which a deletion or rearrangement involving the
chromosome 15q11-13 region can be seen in ,1 percent of

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 FIGURE 1  ■  Characteristic features of Angelman syndrome.
Abbreviation: EEG 5 electroencephalogram.
patients. Molecular testing is done to identify the underlying
genetic cause of AS namely, chromosomal deletion, unipa-
rental disomy, imprinting defect, and UBE3A gene muta-
tion. The three main steps involved in molecular testing are
a methylation test, fluorescent in situ hybridization (FISH),
and restriction fragment length polymorphism (R FLP).
These are summarized in Figure 2.
Assisted Reproductive Technology
and Imprinting Disorders
In the past three decades, there has been a great expansion
in the frequency of assisted reproductive technology (ART)
births.19
Studies have shown that certain procedures, such as intra-
cytoplasmic sperm injection (ICSI) and in vitro fertilization
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(IVF) can have complications. The ICSI procedure skips
almost all of the natural selection and may also cause
mechanical damage to sperm and introduction of the acro-
some and components of the medium in the egg. Studies have
reported a high incidence of birth defects, congenital mal-
formations, low-birth weight, a small risk of cancer, as well
as imprinting disorders namely Beckwith-Wiedemann syn-
drome (BWS) and AS.19
Initial reports in 2002 and 2003 had suggested a specific
association of AS in ART births with ICSI. In a reported
case, molecular analysis on two children conceived by ICSI
and diagnosed with AS has revealed a rare sporadic imprint-
ing defect involving epimutations with loss of methyla-
tion on the maternal chromosome 15 at critical imprinting
control regions (small nuclear ribonucleoprotein polypeptide
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 FIGURE 2  ■  Pathways for diagnostic testing.5

DNA methylation test

Normal Abnormal

UBE3A gene testing FISH

Normal ve Normal ve

AS unlikely UBE3A DNA marker Chromosome

but still possible chromosomal analysis deletion
(10%) mutation
(in 70% of all AS
patients)
Normal ve

Imprinting center Paternal UPD

defect (presumed)

Molecular study
of IC to confirm

This figure represents the step-by-step approach of molecular testing to identify the underlying cause of Angelman syndrome.
Abbreviations: FISH 5 fluorescent in situ hybridization; AS 5 Angelman syndrome; UPD 5 uniparental disomy; IC 5 imprinting center.

N [SNRPN] region in AS).5,20 More recent studies however
are suggesting that ICSI alone might not be the major deter-
minant of the association between ART and imprinting
disorders.
A different plausible hypothesis suggested that in vitro
embryo culture may also cause imprinting defects. Studies
of cultured mouse embryos have revealed loss of imprint-
ing which was enhanced by a particular culture medium.
This suggests that the conditions and media of in vitro
embryo culture may have an influence on the risks of epigen-
etic alterations.21
Another hypothesis suggests that the increased frequency
of imprinting disorders following ART may be because of
an association with infertility and its treatment (e.g., involv-
ing induced ovarian hyperstimulation) rather than with in
vitro embryo culture. Further research is required to define
the effect of embryo culture and other related procedures
and their relation to imprinting disorders and epigenetic
consequences.22
Genetic Counseling
Although in most cases, AS is a sporadic occurrence within
a family, it can be also familial, so genetic counseling should
be offered to all families to discuss their individual case,
including recurrence risks and the risks for other members of
their extended family.12
Determining the recurring risks for AS is both essential
and difficult. Genetic counseling about the recurrence risks
has an impact on reproductive decision making, and families
need to have all the information about the possible recur-
rence of AS in subsequent pregnancies.12
Management of Angelman Syndrome
To date, there is no cure for disorders such as AS because
there are still no definitive ways of repairing chromosomal
defects or of restoring the function of a mutated gene. As a
result, treatment and management of such conditions focus on
managing the physical and neurologic problems of the patients
and providing appropriate educational support.1 In fact, man-
agement of AS is symptomatic, meaning that the therapy itself
is usually aimed at reducing the signs and symptoms of the
syndrome for the comfort and well-being of the patient but
does not address the basic cause of the disease itself.12
Because AS is a multisystem disorder, patients with AS
require multidisciplinary interventions throughout their
lives. The Appendix summarizes some of the management

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 guidelines that should be used in the care of such patients.
These have been divided into different sections according to
different body systems.12
Alternative therapies, such as massage and aromatherapy,
can improve concentration and decrease hyperactivity.1,12
Hippotherapy, hydrotherapy, and music therapy also have
been proven helpful in management of AS patients.12 The
most commonly effective drugs used to treat epilepsy are
benzodiazepines (namely clonazepam), phenobarbital, and
sodium valproate.1,4 Other drugs, including lamotrigine,
topiramate, and levetiracetam, may also be administered to
AS patients suffering from epilepsy.4,12
In contrast, there are certain drugs, such as carbamazepine,
oxcarbazepine, and vigabatrin (an inhibitor of GABA metab-
olism), which have adverse effects on AS patients because
they have been associated with worsening of seizures—
especially myoclonic types. The mechanism is related to
enhancement of neuronal activity within thalamocortical cir-
cuitry.15 Nevertheless, in some cases they might not be com-
pletely contraindicated, especially when the other drugs are
ineffective.4,5,12
A ketogenic diet has shown helpful in certain children
with untreatable epilepsy.4 The ketogenic diet is a high-fat,
adequate-protein, low-carbohydrate diet. The hypothesis
behind using this diet is that the body is forced to bypass mal-
functioning glycolytic pathways and use fat as an alternative
source of energy, which is metabolized into ketones bodies
that can cross the blood-brain barrier. These are possible
anticonvulsant in themselves.4,12,16,17
Neonatal nurses play a role in supporting the parents of
the infant at a time when they are very anxious and stressed,
especially at time of diagnosis. Parents should be encouraged
to take an active role in the management of their infant’s
condition.
Self-Help Skills
Self-help skills are part of the management for AS, and
they vary in different patients. Most of the patients learn
to communicate their likes and dislikes and to walk. They
learn to make choices regarding the food they eat and the
clothes they wear. However, help is needed with dressing
and bathing. Moreover, by using basic utensils, people with
AS manage to feed themselves.1 Also, standard toilet train-
ing regimes are successful in children with learning disabili-
ties. In .50 percent of AS children, daytime continence can
be achieved, but in ,20 percent at night.12 All the patients
require round-the-clock supervision because they have no
sense of danger; however, they still lead a semi-independent
existence with a good quality of life.1
Prognosis
Although all individuals with AS will have developmental
delays, speech, and motor impairments, there is a significant
variation in the severity of the symptoms among the popu-
lation of those affected. In fact, some speech and a higher
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degree of self-help skills are possible among particular AS
patients. The severity of the symptoms and the general prog-
nosis are correlated with the specific genetic mechanism
underlying the syndrome. Those involving large chromo-
somal deletions on chromosome 15 will have more severe
symptoms than those with a UBE3A gene mutation.1
Individuals with AS can have a normal life span and gener-
ally do not show developmental regression as they get older.
They can have a good quality of life with early diagnosis and
appropriate interventions, therapies, and constant attention
(because they lack a sense of danger). AS is not a degenera-
tive disorder, and many patients improve their living skills
with support.1 The prognosis of AS patients can be improved
significantly by early and continued participation in physical,
occupational (associated with developing motor control skills),
and speech (communication) therapies. Medication is advis-
able, especially to those with seizures and poor sleep patterns.
Another feature in the prognosis of an AS patient is that
the clinical features alter with age. In adulthood, hyperactiv-
ity and poor sleep patterns improve, the frequency of seizures
decrease and often may cease completely, and EEG abnor-
malities are less distinct.5
Puberty and menstruation commence at the average age
and sexual development seems to be unaffected as evidenced
by a case where a woman with AS had a child, who also
had AS.5
A common problem that may arise in adulthood is the ten-
dency to obesity (more frequent in females). This may worsen
mobility and the development or worsening of scoliosis, which
is treated with bracing and possibly surgical correction.5
Research and Clinical Trials
When AS was initially described, very little was known
about its genetic and neurophysiologic aspects. However,
once significant findings about these two aspects were discov-
ered, the interest in the syndrome and the need for research
studies increased.23
Further research studies are still needed to completely
understand the connection between the phenotype revealed
in AS and the lack of expression of the UBE3A gene at the
molecular level. This additional understanding may shed
light on potential therapeutic up-regulation and may help
us come up with targeted intervention. Finally, more clinical
research is required to better manage epilepsy, motor impair-
ment, and sleep disturbances and improve behavior, learning,
and communication difficulties.23
The neonatal nurse may also be involved in clinical
research. This role is complex but vital and very interesting.
They require leadership and organizational skills to develop
multidisciplinary teams that deliver the research. They may
be important in coordinating the initiation and completion
of the research.24
Such nurses have a vast variety of roles, including data col-
lection, follow-up of patients, preparing trial protocols, docu-
mentation, and acquire fully informed consent from patients
4/28/17 2:07 PM
 or their relatives before enrolling to trials. Nurses may also
screen for potential participants at outpatient clinics.24
Future Management
To cure any kind of disorder, an insight into what is going
wrong in the body is critical. In the case of AS, much of its
pathophysiology has been discovered. It is known that the
gene product UBE3A is not produced in certain neurons in
the brain. This causes severe learning disabilities and motor
impairments in AS individuals.25
All the symptoms of AS are caused by the loss of UBE3A
activity; therefore, one can focus on finding a therapy that
will restore UBE3A function in neurons. There are excellent
animal models for AS that can help researchers learn more.
Experimental research in these animal models has shown that
AS can be cured.25
It is also known that loss of UBE3A affects only neuro-
nal function, not neuronal development, meaning that the
neurons and the brain of an AS individual form correctly.
This is very important because if UBE3A could be restored,
the neurons could function normally. One of the main strate-
gies of restoring UBE3A activity in neurons of AS individuals
is to turn on the paternal UBE3A allele, which is still com-
pletely normal although silenced. Current research is directed
at finding the right drug or treatment to achieve this.26
Drug screening has been implemented to identify com-
pounds that are able to activate the paternal UBE3A copy in
a mouse model of AS. The neurons of the mice used in the
experiment expressed a fluorescent form of UBE3A in response
to drugs that switched on the gene’s paternal copy. 26,27
Particularly when a topoisomerase inhibitor named topote-
can was infused in mice for two weeks, the UBE3A paternal
copy was activated throughout the brain.26,28 The UBE3A
gene on the paternal chromosome is silenced by an “anti-
sense” RNA transcript, whose expression is regulated by an
imprinting control center. On the maternal chromosome,
this control center and its promoter region are methylated,
suppressing transcription of the antisense RNA and avoid-
ing silencing of the maternal UBE3A gene. In contrast, the
control center on the paternal chromosome is not methyl-
ated, permitting transcription to take place and consequently
silencing the paternal UBE3A. Methylation of the control
center on the paternal chromosome is only slightly changed
by topotecan; however, this drug still leads to a remarkable
reduction in the expression of the antisense RNA, and hence
a decreased silencing effect of the UBE3A gene.26
This type of treatment is still at a research phase because
a risk-benefit assessment must also be considered. Additional
safety and dosage information is needed before this drug
is injected into children. Moreover, this type of treatment
would mostly be beneficial for the youngest infants because
brain development is mostly active in the early years of life.26
Another strategy to restore neuronal function is to correct
other complications caused as a result of UBE3A loss, such
as the loss of CaMKII activity which results in learning
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deficiency and lack of memory formation. Therefore, finding
drugs that can enhance CaMKII activity in neurons could
also help individuals with AS.25
Being a rare syndrome, campaigning for research funding
is limited because there are far more common disorders,
such as autism, on which to focus. Moreover, pharmaceutical
companies are not willing to invest much time and money
to develop therapeutics that would have a limited market.25
Curing AS can provide opportunities and knowledge for
learning more about the etiology of other neurologic disor-
ders such as autism and Alzheimer’s disease, as well as provid-
ing therapeutic strategies for disorders such as Rett syndrome
and fragile X syndrome.25
REFERENCES
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and genetic aspects. J Med Genet. 2003;40:87-95.
  2. Van Buggenhout G, Fryns JP. Angelman syndrome (AS, MIM 105830).
Eur J Hum Genet. 17;2009:1367-1373.
  3. Magenis RE, Brown MG, Lacy DA, Budden S, LaFranchi S. Is Angelman
syndrome an alternate result of del(15)(q11q13)? Am J Med Genet.
1987;28(4):829-838.
  4. Fiumara A, Pittalà A, Cocuzza M, Sorge G. Epilepsy in patients with
Angelman syndrome. Ital J Pediatr. 2010;36:31. http://dx.doi
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  5. Williams CA, Peters S, Calculator S. Facts about Angelman syndrome.
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Accessed January 12, 2014.
  6. Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome:
insights into genomic imprinting and neurodevelopmental phenotypes.
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 7. Jana NR. Understanding the pathogenesis of Angelman syndrome
through animal models. Neural Plast. 2012;2012:710943. http://
dx.doi.org/10.1155/2012/710943
 8. Lobo I. Same genetic mutation, different genetic disease phenotype.
Nature Education. 2008;1(1):64.
  9. Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL. The Angelman
syndrome ubiquitin ligase localizes to the synapse and nucleus, and
maternal deficiency results in abnormal dendritic spine morphology.
Hum Mol Genet. 2008;17:111-118.
10. Philpot BD, Thompson CE, Franco L, Williams CA. Angelman
syndrome: advancing the research frontier of neurodevelopmental
disorders. J Neurodev Disord. 2011;3:50-56.
11. Kaphzan H, Hernandez P, Jung JI, et al. Reversal of impaired hippocampal
long-term potentiation and contextual fear memory deficits in Angelman
syndrome model mice by ErbB inhibitors. Biol Psychiatry. 2012;
72:182-190.
12. Clayton-Smith J, Adams D, Dan B, Emerson F, Hood K. Management
of Angelman syndrome: a clinical guideline. Orphanet website. https://
www.orpha.net/data/patho/Pro/en/AngelmanGuidelines2011.pd.
Accessed January 14, 2014.
13. Pelc K, Dan B. Natural history of Angelman syndrome. In: Dan B,
ed. Angelman Syndrome. London, United Kingdom: Mac Keith Press;
2008: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2008
00392.x/pdf; pp. 392-395. Accessed January 13, 2014.
14. Health Careers. Neonatal nurses. Health Careers website. https://www
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2005;5(5):192-193.
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of the ketogenic diet. Pediatr Neurology. 2007;36(5):281-292.
17. Evangeliou A, Doulioglou V, Haidopoulou K, Aptouramani M,
Spilioti M, Varlamis G. Ketogenic diet in a patient with Angelman
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10.1111/j.1442-200X.2010.03118.x
18. Kara B, Karaman B, Ozmen M, et al. Angelman syndrome: clinical findings
and follow-up data of 14 patients. Turk J Pediatr. 2008;50(2):137-142.
19. Talaulikar VS, Arulkumaran S. Reproductive outcomes after assisted
conception. Obstet Gynecol Surv. 2012;67:566-583.
20. Cox GF, Bürger J, Lip V, et al. Intracytoplasmic sperm injection may increase
the risk of imprinting defects. Am J Hum Genet. 2002;71:162-164.
21. Mann MR, Lee SS, Doherty AS, et al. Selective loss of imprinting in the
placenta following preimplantation development in culture. Development.
2007;131:3727-3735.
22. Maher ER, Brueton LA, Bowdin SC Beckwith-Wiedemann syndrome and
assisted reproduction technology (ART). J Med Genet. 2003;40:62-64.
23. Dan B. Angelman syndrome: current understanding and research
prospects. Epilepsia. 2009;50:2331-2339.
24. National Institute of Health Research. Clinical research nurses. National
Institute of Health Research website. http://www.nihr.ac.uk/our-
faculty/clinical-research-staff/clinical-research-nurses/. Updated July 28,
2015. Accessed July 4, 2016.
25. Foundation for Angelman Syndrome Therapeutics. Why there is hope for a
cure. Foundation for Angelman Syndrome Therapeutics website. http://
www.cureangelman.org/what-hope.html. Accessed February 14, 2014.
26. Beaudet AL. Angelman syndrome: drugs to awaken a paternal gene.
Nature. 2011;481:150-152.
27. Braam W, Smits M, Didden R, Curfs L. Melatonin is effective in treating
sleep problems in Angelman syndrome but problems in metabolising
melatonin may be part of the Angelman phenotype. J Intellect Disabil
Res. 2008;52(10):814.
28. Huang HS, Allen JA, Mabb AM, et al. Topoisomerase inhibitors unsilence
the dormant allele of Ube3a in neurons. Nature. 2012;481:185-189.
About the Authors
Daniela Bonello and Francesca Camilleri are both final-year
medical students working on a project on congenital imprinting disor-
ders, under the supervision of Professor Jean Calleja-Agius.
Jean Calleja-Agius, MD, MRCOG, MRCPI, MSc, PhD, is cur-
rently the head of Department of Anatomy at the University of Malta,
where she teaches embryology to under- and postgraduate health care
professionals. She is currently involved in research into congenital
imprinting disorders as part of the European Network for Human
Congenital Imprinting Disorders.
For further information, please contact:
Jean Calleja-Agius, MD, MRCOG, MRCPI, MSc, PhD
University of Malta
Department of Anatomy
Msida MSD 2080
MALTA
E-mail: jean.calleja-agius@um.edu.mt

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 APPENDIX

Management and Therapeutic Guidelines for Angelman Syndrome2,12

1.  Feeding and Diet
Feeding problems in newborns and infants—sucking is Use of special nipples
ineffective; therefore, breast feeding may be problematic. Weight gain monitored carefully
Referral to specialized teams for advice and training on feeding
Gastroesophageal reflux both in childhood and adulthood Upright positioning or specific motility medications
Administration of antireflux medications such as aluminium hydroxide/
magnesium carbonate (e.g., Gaviscon)
Constipation Fiber-rich diet and laxative agents
Increased fluid intake or jelly as an alternative
Obesity Weight and BMI checked regularly
A regular exercise program should be included in the patient’s daily activities
2.  Physical and Speech Development and Communication
General developmental delay in childhood Organization of an early, individualized and active intervention program
Appropriate scales, such as Bayley, must be used to assess development
Lack of fine motor and gross motor control skills Occupational and physical therapy needed to stimulate these motor control
skills and to manage balance, posture, and muscle contractures
Poorly developed active communication Speech and language therapy including nonverbal methods of
communication, picture cards, or communication boards
Communication must be functional, that is, communicating needs and
expressing choices rather than just naming
3. Seizures
Seizures Administration of anticonvulsant medications
For more specific treatment, refer to section about seizures and EEG
4. Sleep
Severe sleep problems Avoid stimulatory activities before bedtime, such as TV
Maintain the same bedtime routine
Sedative medication, usually melatonin, to promote sleep in AS patients*
5. Vision
Ocular problems Visual assessment is important to encourage interaction and diminish autistic
and self-mutilative tendencies
Strabismus—common in younger children Referral to an ophthalmologist

Abbreviations: BMI 5 body mass index; EEG 5 electroencephalogram.

*Although melatonin is the medication most mentioned in the reviews, it was observed that the beneficial effect of melatonin is lost after several
weeks in most patients with AS.27

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