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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

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

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from the father. In certain areas of the brain, the paternal Neurophysiology of Angelman Syndrome
copy of the gene is inactivated by the normal process of There is evidence that the neurologic deficits observed in
genomic imprinting, and as a result, only one working copy AS patients may result from specific abnormalities in synaptic
of the gene is inherited.6 development and plasticity.9 Experiments carried out on AS
A mutation in the remaining active maternally derived mice models have shown that UBE3A is required for cortical
gene prevents the formation of the enzyme in the brain. The plasticity and experience-driven plasticity. The experiments
loss of enzyme function is therefore the underlying molecular show reduced dendritic spine density and length which may
mechanism responsible for most cases of AS and the most be relevant to the cognitive deficits and motor impairment.10
likely cause of the features observed in AS.5 Mice models have also demonstrated deficits in hippocampal
In the sister syndrome, Prader-Willi Syndrome (PWS), long-term potentiation (LTP) and deficits in hippocampus-
imprinting occurs on the maternally derived allele of the dependent memory that likely explains the learning and
same locus (15q11-q13), and mutations on the paternal allele memory impairment in patients with AS.11
are responsible for the manifestation of PWS.5
There are four different mutational mechanisms known Signs and Symptoms
to cause AS, all of which affect and interfere with maternal The characteristic signs and symptoms of AS evolve slowly
UBE3A gene expression at the 15q11-13 locus.7 As shown with age. Initially, there is overlap with features of other dis-
in Table 1, patients are grouped into five classes according to orders, some of which are listed in Table 2. As a result of this,
the pathophysiology of the syndrome.5 most AS cases are not diagnosed during early infancy because
When compared with the other classes, Class I patients the developmental problems are still very nonspecific during
with a chromosomal deletion present the worst clinical phe- this period.2,4,5,12
notype (e.g., motor difficulties, microcephaly, seizures, and Developmental and physical characteristics have been
speech impairment).2 Approximately 70 percent of patients described to establish clinical criteria for the diagnosis of
have a de novo deletion on the 15q11-13 maternal chromo- AS syndrome, as shown in Table 3. 5 However, these clin-
some. These deletions have common breakpoints and are ical criteria are not absolute proof of diagnosis and ulti-
of similar size of approximately 4 megabases (Mb). A few mately the condition should always be confirmed by genetic
patients have similar but slightly different deletions arising de testing.12
novo or as unbalanced translocations.8 As soon as a baby is born, neonatal nurses should be
Individuals suffering from AS may exhibit different attuned to specif ic physical/dysmorphic features. This
signs and symptoms of different severity. This is because requires knowledge not only of AS but of other genetic con-
of variable expressivity and penetrance, where the same ditions. A full neurologic exam should be carried out and
mutation is not always expressed to the same extent in the nurses should especially observe for hypotonia, and sucking
individuals who carry it. Some examples of phenotype vari- and swallowing difficulties. The neonate may have difficulty
ability resulting from variance in gene structure include: in establishing breastfeeding. These problems account for
(1) loss of the HERC2 gene transcript during the deletion the most frequent reasons for NICU admissions of these
is responsible for blue eyes in many AS patients; and (2) babies. Nonetheless, such features, especially if mild, can also
the deletion of the OCA2 gene, whose protein determines be observed in normal infants or in those presenting with
the pigmentation of the skin, eyes, and hair and which is other conditions. Moreover, the more characteristic fea-
also located on the chromosome 15, is responsible for the tures of AS present later on in childhood and therefore early
light-colored hair and fair skin observed in AS patients. investigations, such as genetic studies are not warranted.13
Phenotype variability may make the diagnosis of AS more The role of neonatal nurses may extend beyond this period,
challenging. 5 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
TABLE 1  ■  The Different Classes of Genetic Mechanisms Leading to from one patient to another. Many patients have normal pig-
Angelman Syndrome5 mentation, whereas others have a normal head circumference.
Class Genetic Mechanism Frequency (%) Seizures may be absent in some cases, and in others, some
degree of speech may be present. Moreover, the characteristic
I Deletion 70–75
dysmorphic face may not be present in certain patients, who
II Uniparental disomy 2–3 would also have minimal ataxia.1
III Imprinting defect 3–5 The most consistent and striking clinical features are the
IV UBE3A mutation 5–10 behavioral ones, and for this reason, these are the characteristics
V Unknown 10–15 that usually prompt clinicians to consider the diagnosis of AS.1
The physical and behavioral features that are manifested
Other chromosome rearrangements 1–2
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 As a result of severe mental retardation and delayed devel-
and clear from the age of 1 year.1 Children with AS experi- opmental milestones, children with AS fail to acquire motor,
ence puberty at the expected age, and they develop normal cognitive, and language skills. Although social development
secondary sexual characteristics.1 may also lag behind, children with AS do acquire some social
Adult A S patients show pronounced mandibular skills and manage to fit in well with other children.1,15
prognathism, pointed chin, macrostomia, and prominent Because of delayed motor development, muscle tone in AS
lower lip.1,2 Moreover, in some, eyes may become more patients is abnormal. They show truncal hypotonia because
deeply set.1 However, other features, such as ataxia, become of weak and inflexible muscles of the trunk and also hyperto-
less striking as the patients develop reduced mobility because nicity of the limbs and brisk reflexes.1
of limb hypertonicity and thoracic scoliosis.1,2 Seizures and abnormal electroencephalogram (EEG)
Even though in late childhood and adolescence the fre- patterns are characteristic signs of AS which lead to an early
quency of seizures may decrease, most adults still experience diagnosis. Most patients present with epileptic seizures
seizures mainly myoclonic and atypical absence seizures.1,2 during the first three years of life.4
With progression into adulthood, the behavior changes as In childhood, all types of seizures have been described,
well. Hyperactivity is reduced, attention span increases, ranging from jerky movements of all extremities to brief
and sleeping problems improve. 2 Certain adult patients periods of lack of awareness. However, the types of seizures
may exhibit an aggressive behavior and frustration espe- typical of AS are atypical absences, myoclonic seizures, and
cially when finding it difficult to communicate.1 In fact, in nonconvulsive status epilepticus (NCSE). Atypical absences
most AS patients, speech does not develop, and therefore, are considered as staring spells which may be difficult to dis-
communication difficulties are a prominent feature of this tinguish from the usual behavior of an individual. Myoclonic
syndrome. Patients may have a vocabulary of two or three seizures are brief jerks of a single muscle or a group of
words only.1 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 in head circumference, leading to Protruding tongue
use of words; nonverbal and receptive microcephaly by the age of two years;
this being more pronounced in those with Tongue thrusting; suck/swallowing disorders
communication skills are higher than
verbal ones 15q11.2-q13 deletions Feeding problems during infancy
Movement disorder, usually ataxic and/or Onset of seizures, usually ,3 years of age Truncal hypotonia
tremulous movement of the limbs A characteristic EEG pattern with large Prognathia
Unique behavioral features: a combination amplitude slow spike waves and triphasic Wide mouth, widely spaced teeth
of frequent and inappropriate laughter, waves
Frequent drooling
easily excitable personality, often with
hand flapping movements and short Excessive chewing/mouthing behaviors
attention span 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 and symptoms evolve with age and overlap with those of
Although the pathogenesis of epilepsy in AS is not fully other disorders. 2 The characteristic features are shown in
understood, GABAergic dysfunction has been hypothesized Figure 1.
to contribute to the presence of epilepsy and neurotransmis- Behavioral characteristics such as a happy demeanor, par-
sion impairment in many patients with AS.4 oxysmal laughter, sleeping problems, and hyperactivity are
Specific EEG anomalies are observed in AS patients, quite striking in these patients, and they are the first features
which, together with epileptic crises, help early diagno- to be analyzed by clinicians in their diagnosis.2 Early diagno-
sis of AS. Three typical patterns are mainly observed in sis is important for early therapeutic intervention especially of
very early infancy, namely, persistent generalized rhythmic epileptic seizures and for genetic counseling.18
4–6 Hz activity reaching more than 200 mV of amplitude, It has been suggested that to make a good diagnosis, the
not associated with drowsiness, prolonged rhythmic delta observable traits of AS should be assessed using measurable
(triphasic) activity of 2–3 Hz with a moderate amplitude criteria in at least five domains: intellectual function, lan-
of 200–500 mV, more evident over the frontal regions and guage and speech, attention span, social impairments, and
mixed with spikes or sharp waves; and spikes and sharp waves other behavioral disturbances.5
mixed with 3–4 Hz components, usually with amplitude of
more than 200 mV, are mainly seen posteriorly and are facili- Diagnostic Tests
tated by or only seen on eye closure.1,4 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
DIAGNOSIS help in the diagnosis of AS.
The diagnosis of AS is based on clinical, behavioral, and The cytogenetic approach involves routine analysis of chro-
developmental phenotypes, as well as laboratory genetic mosomes by which a deletion or rearrangement involving the
tests. 2 An AS is diff icult to diagnose because the signs 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 (IVF) can have complications. The ICSI procedure skips
genetic cause of AS namely, chromosomal deletion, unipa- almost all of the natural selection and may also cause
rental disomy, imprinting defect, and UBE3A gene muta- mechanical damage to sperm and introduction of the acro-
tion. The three main steps involved in molecular testing are some and components of the medium in the egg. Studies have
a methylation test, fluorescent in situ hybridization (FISH), reported a high incidence of birth defects, congenital mal-
and restriction fragment length polymorphism (R FLP). formations, low-birth weight, a small risk of cancer, as well
These are summarized in Figure 2. as imprinting disorders namely Beckwith-Wiedemann syn-
drome (BWS) and AS.19
Assisted Reproductive Technology Initial reports in 2002 and 2003 had suggested a specific
and Imprinting Disorders association of AS in ART births with ICSI. In a reported
In the past three decades, there has been a great expansion case, molecular analysis on two children conceived by ICSI
in the frequency of assisted reproductive technology (ART) and diagnosed with AS has revealed a rare sporadic imprint-
births.19 ing defect involving epimutations with loss of methyla-
Studies have shown that certain procedures, such as intra- tion on the maternal chromosome 15 at critical imprinting
cytoplasmic sperm injection (ICSI) and in vitro fertilization 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 be offered to all families to discuss their individual case,
are suggesting that ICSI alone might not be the major deter- including recurrence risks and the risks for other members of
minant of the association between ART and imprinting their extended family.12
disorders. Determining the recurring risks for AS is both essential
A different plausible hypothesis suggested that in vitro and difficult. Genetic counseling about the recurrence risks
embryo culture may also cause imprinting defects. Studies has an impact on reproductive decision making, and families
of cultured mouse embryos have revealed loss of imprint- need to have all the information about the possible recur-
ing which was enhanced by a particular culture medium. rence of AS in subsequent pregnancies.12
This suggests that the conditions and media of in vitro
embryo culture may have an influence on the risks of epigen- Management of Angelman Syndrome
etic alterations.21 To date, there is no cure for disorders such as AS because
Another hypothesis suggests that the increased frequency there are still no definitive ways of repairing chromosomal
of imprinting disorders following ART may be because of defects or of restoring the function of a mutated gene. As a
an association with infertility and its treatment (e.g., involv- result, treatment and management of such conditions focus on
ing induced ovarian hyperstimulation) rather than with in managing the physical and neurologic problems of the patients
vitro embryo culture. Further research is required to define and providing appropriate educational support.1 In fact, man-
the effect of embryo culture and other related procedures agement of AS is symptomatic, meaning that the therapy itself
and their relation to imprinting disorders and epigenetic is usually aimed at reducing the signs and symptoms of the
consequences.22 syndrome for the comfort and well-being of the patient but
does not address the basic cause of the disease itself.12
Genetic Counseling Because AS is a multisystem disorder, patients with AS
Although in most cases, AS is a sporadic occurrence within require multidisciplinary interventions throughout their
a family, it can be also familial, so genetic counseling should lives. The Appendix summarizes some of the management

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guidelines that should be used in the care of such patients. degree of self-help skills are possible among particular AS
These have been divided into different sections according to patients. The severity of the symptoms and the general prog-
different body systems.12 nosis are correlated with the specific genetic mechanism
Alternative therapies, such as massage and aromatherapy, underlying the syndrome. Those involving large chromo-
can improve concentration and decrease hyperactivity.1,12 somal deletions on chromosome 15 will have more severe
Hippotherapy, hydrotherapy, and music therapy also have symptoms than those with a UBE3A gene mutation.1
been proven helpful in management of AS patients.12 The Individuals with AS can have a normal life span and gener-
most commonly effective drugs used to treat epilepsy are ally do not show developmental regression as they get older.
benzodiazepines (namely clonazepam), phenobarbital, and They can have a good quality of life with early diagnosis and
sodium valproate.1,4 Other drugs, including lamotrigine, appropriate interventions, therapies, and constant attention
topiramate, and levetiracetam, may also be administered to (because they lack a sense of danger). AS is not a degenera-
AS patients suffering from epilepsy.4,12 tive disorder, and many patients improve their living skills
In contrast, there are certain drugs, such as carbamazepine, with support.1 The prognosis of AS patients can be improved
oxcarbazepine, and vigabatrin (an inhibitor of GABA metab- significantly by early and continued participation in physical,
olism), which have adverse effects on AS patients because occupational (associated with developing motor control skills),
they have been associated with worsening of seizures— and speech (communication) therapies. Medication is advis-
especially myoclonic types. The mechanism is related to able, especially to those with seizures and poor sleep patterns.
enhancement of neuronal activity within thalamocortical cir- Another feature in the prognosis of an AS patient is that
cuitry.15 Nevertheless, in some cases they might not be com- the clinical features alter with age. In adulthood, hyperactiv-
pletely contraindicated, especially when the other drugs are ity and poor sleep patterns improve, the frequency of seizures
ineffective.4,5,12 decrease and often may cease completely, and EEG abnor-
A ketogenic diet has shown helpful in certain children malities are less distinct.5
with untreatable epilepsy.4 The ketogenic diet is a high-fat, Puberty and menstruation commence at the average age
adequate-protein, low-carbohydrate diet. The hypothesis and sexual development seems to be unaffected as evidenced
behind using this diet is that the body is forced to bypass mal- by a case where a woman with AS had a child, who also
functioning glycolytic pathways and use fat as an alternative had AS.5
source of energy, which is metabolized into ketones bodies A common problem that may arise in adulthood is the ten-
that can cross the blood-brain barrier. These are possible dency to obesity (more frequent in females). This may worsen
anticonvulsant in themselves.4,12,16,17 mobility and the development or worsening of scoliosis, which
Neonatal nurses play a role in supporting the parents of is treated with bracing and possibly surgical correction.5
the infant at a time when they are very anxious and stressed,
especially at time of diagnosis. Parents should be encouraged Research and Clinical Trials
to take an active role in the management of their infant’s When AS was initially described, very little was known
condition. about its genetic and neurophysiologic aspects. However,
once significant findings about these two aspects were discov-
Self-Help Skills ered, the interest in the syndrome and the need for research
Self-help skills are part of the management for AS, and studies increased.23
they vary in different patients. Most of the patients learn Further research studies are still needed to completely
to communicate their likes and dislikes and to walk. They understand the connection between the phenotype revealed
learn to make choices regarding the food they eat and the in AS and the lack of expression of the UBE3A gene at the
clothes they wear. However, help is needed with dressing molecular level. This additional understanding may shed
and bathing. Moreover, by using basic utensils, people with light on potential therapeutic up-regulation and may help
AS manage to feed themselves.1 Also, standard toilet train- us come up with targeted intervention. Finally, more clinical
ing regimes are successful in children with learning disabili- research is required to better manage epilepsy, motor impair-
ties. In .50 percent of AS children, daytime continence can ment, and sleep disturbances and improve behavior, learning,
be achieved, but in ,20 percent at night.12 All the patients and communication difficulties.23
require round-the-clock supervision because they have no The neonatal nurse may also be involved in clinical
sense of danger; however, they still lead a semi-independent research. This role is complex but vital and very interesting.
existence with a good quality of life.1 They require leadership and organizational skills to develop
multidisciplinary teams that deliver the research. They may
Prognosis be important in coordinating the initiation and completion
Although all individuals with AS will have developmental of the research.24
delays, speech, and motor impairments, there is a significant Such nurses have a vast variety of roles, including data col-
variation in the severity of the symptoms among the popu- lection, follow-up of patients, preparing trial protocols, docu-
lation of those affected. In fact, some speech and a higher mentation, and acquire fully informed consent from patients

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or their relatives before enrolling to trials. Nurses may also deficiency and lack of memory formation. Therefore, finding
screen for potential participants at outpatient clinics.24 drugs that can enhance CaMKII activity in neurons could
also help individuals with AS.25
Future Management Being a rare syndrome, campaigning for research funding
To cure any kind of disorder, an insight into what is going is limited because there are far more common disorders,
wrong in the body is critical. In the case of AS, much of its such as autism, on which to focus. Moreover, pharmaceutical
pathophysiology has been discovered. It is known that the companies are not willing to invest much time and money
gene product UBE3A is not produced in certain neurons in to develop therapeutics that would have a limited market.25
the brain. This causes severe learning disabilities and motor Curing AS can provide opportunities and knowledge for
impairments in AS individuals.25 learning more about the etiology of other neurologic disor-
All the symptoms of AS are caused by the loss of UBE3A ders such as autism and Alzheimer’s disease, as well as provid-
activity; therefore, one can focus on finding a therapy that ing therapeutic strategies for disorders such as Rett syndrome
will restore UBE3A function in neurons. There are excellent and fragile X syndrome.25
animal models for AS that can help researchers learn more.
Experimental research in these animal models has shown that
AS can be cured.25 REFERENCES
It is also known that loss of UBE3A affects only neuro-   1. Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical
nal function, not neuronal development, meaning that the and genetic aspects. J Med Genet. 2003;40:87-95.
neurons and the brain of an AS individual form correctly.   2. Van Buggenhout G, Fryns JP. Angelman syndrome (AS, MIM 105830).
This is very important because if UBE3A could be restored, Eur J Hum Genet. 17;2009:1367-1373.
the neurons could function normally. One of the main strate-   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.
gies of restoring UBE3A activity in neurons of AS individuals
1987;28(4):829-838.
is to turn on the paternal UBE3A allele, which is still com-
  4. Fiumara A, Pittalà A, Cocuzza M, Sorge G. Epilepsy in patients with
pletely normal although silenced. Current research is directed Angelman syndrome. Ital J Pediatr. 2010;36:31. http://dx.doi
at finding the right drug or treatment to achieve this.26 .org/10.1186/1824-7288-36-31
Drug screening has been implemented to identify com-   5. Williams CA, Peters S, Calculator S. Facts about Angelman syndrome.
pounds that are able to activate the paternal UBE3A copy in Angelman Syndrome Foundation website. http://www.angelman.org/
a mouse model of AS. The neurons of the mice used in the wp-content/uploads/2015/11/facts_about_as_2009_3-19-10.pdf.
Accessed January 12, 2014.
experiment expressed a fluorescent form of UBE3A in response
  6. Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome:
to drugs that switched on the gene’s paternal copy. 26,27
insights into genomic imprinting and neurodevelopmental phenotypes.
Particularly when a topoisomerase inhibitor named topote- Trends Neurosci. 2011;34:293-303.
can was infused in mice for two weeks, the UBE3A paternal  7. Jana NR. Understanding the pathogenesis of Angelman syndrome
copy was activated throughout the brain.26,28 The UBE3A through animal models. Neural Plast. 2012;2012:710943. http://
gene on the paternal chromosome is silenced by an “anti- dx.doi.org/10.1155/2012/710943
sense” RNA transcript, whose expression is regulated by an  8. Lobo I. Same genetic mutation, different genetic disease phenotype.
imprinting control center. On the maternal chromosome, Nature Education. 2008;1(1):64.
this control center and its promoter region are methylated,   9. Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL. The Angelman
syndrome ubiquitin ligase localizes to the synapse and nucleus, and
suppressing transcription of the antisense RNA and avoid-
maternal deficiency results in abnormal dendritic spine morphology.
ing silencing of the maternal UBE3A gene. In contrast, the Hum Mol Genet. 2008;17:111-118.
control center on the paternal chromosome is not methyl- 10. Philpot BD, Thompson CE, Franco L, Williams CA. Angelman
ated, permitting transcription to take place and consequently syndrome: advancing the research frontier of neurodevelopmental
silencing the paternal UBE3A. Methylation of the control disorders. J Neurodev Disord. 2011;3:50-56.
center on the paternal chromosome is only slightly changed 11. Kaphzan H, Hernandez P, Jung JI, et al. Reversal of impaired hippocampal
by topotecan; however, this drug still leads to a remarkable long-term potentiation and contextual fear memory deficits in Angelman
syndrome model mice by ErbB inhibitors. Biol Psychiatry. 2012;
reduction in the expression of the antisense RNA, and hence
72:182-190.
a decreased silencing effect of the UBE3A gene.26
12. Clayton-Smith J, Adams D, Dan B, Emerson F, Hood K. Management
This type of treatment is still at a research phase because of Angelman syndrome: a clinical guideline. Orphanet website. https://
a risk-benefit assessment must also be considered. Additional www.orpha.net/data/patho/Pro/en/AngelmanGuidelines2011.pd.
safety and dosage information is needed before this drug Accessed January 14, 2014.
is injected into children. Moreover, this type of treatment 13. Pelc K, Dan B. Natural history of Angelman syndrome. In: Dan B,
would mostly be beneficial for the youngest infants because ed. Angelman Syndrome. London, United Kingdom: Mac Keith Press;
2008: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2008
brain development is mostly active in the early years of life.26
00392.x/pdf; pp. 392-395. Accessed January 13, 2014.
Another strategy to restore neuronal function is to correct
14. Health Careers. Neonatal nurses. Health Careers website. https://www
other complications caused as a result of UBE3A loss, such .healthcareers.nhs.uk/explore-roles/nursing/neonatal-nurse. Accessed
as the loss of CaMKII activity which results in learning July 4, 2016.

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15. French JA. Seizure exacerbation by antiepileptic drugs. Epilepsy Curr. 26. Beaudet AL. Angelman syndrome: drugs to awaken a paternal gene.
2005;5(5):192-193. Nature. 2011;481:150-152.
16. Hartman AL, Gasior M, Vining EP, Rogawski MA. The neuropharmacology 27. Braam W, Smits M, Didden R, Curfs L. Melatonin is effective in treating
of the ketogenic diet. Pediatr Neurology. 2007;36(5):281-292. sleep problems in Angelman syndrome but problems in metabolising
17. Evangeliou A, Doulioglou V, Haidopoulou K, Aptouramani M, melatonin may be part of the Angelman phenotype. J Intellect Disabil
Spilioti M, Varlamis G. Ketogenic diet in a patient with Angelman Res. 2008;52(10):814.
syndrome. Pediatr Int. 2010;52(5):831-834. http://dx.doi.org/ 28. Huang HS, Allen JA, Mabb AM, et al. Topoisomerase inhibitors unsilence
10.1111/j.1442-200X.2010.03118.x the dormant allele of Ube3a in neurons. Nature. 2012;481:185-189.
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
About the Authors
conception. Obstet Gynecol Surv. 2012;67:566-583. Daniela Bonello and Francesca Camilleri are both final-year
medical students working on a project on congenital imprinting disor-
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.
ders, under the supervision of Professor Jean Calleja-Agius.
Jean Calleja-Agius, MD, MRCOG, MRCPI, MSc, PhD, is cur-
21. Mann MR, Lee SS, Doherty AS, et al. Selective loss of imprinting in the
placenta following preimplantation development in culture. Development.
rently the head of Department of Anatomy at the University of Malta,
2007;131:3727-3735. where she teaches embryology to under- and postgraduate health care
22. Maher ER, Brueton LA, Bowdin SC Beckwith-Wiedemann syndrome and
professionals. She is currently involved in research into congenital
assisted reproduction technology (ART). J Med Genet. 2003;40:62-64. imprinting disorders as part of the European Network for Human
23. Dan B. Angelman syndrome: current understanding and research
Congenital Imprinting Disorders.
prospects. Epilepsia. 2009;50:2331-2339.
For further information, please contact:
24. National Institute of Health Research. Clinical research nurses. National
Jean Calleja-Agius, MD, MRCOG, MRCPI, MSc, PhD
Institute of Health Research website. http://www.nihr.ac.uk/our-
faculty/clinical-research-staff/clinical-research-nurses/. Updated July 28,
University of Malta
2015. Accessed July 4, 2016. Department of Anatomy
25. Foundation for Angelman Syndrome Therapeutics. Why there is hope for a
Msida MSD 2080
cure. Foundation for Angelman Syndrome Therapeutics website. http:// MALTA
www.cureangelman.org/what-hope.html. Accessed February 14, 2014. 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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