The Turkish Journal of Pediatrics
[Mail to Editor ]
Angelman syndrome: clinical findings and follow-up data of 14 patients
Bülent Kara1, Birsen Karaman2, Meral Özmen3, Rasim Özgür Rosti2, Mine Çalışkan3, Hülya Kayserili2, Seher Başaran2
1Department of Pediatrics, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
2Departments of Medical Genetics, İstanbul University İstanbul Faculty of Medicine, İstanbul, Turkey
3Departments of Pediatrics, İstanbul University İstanbul Faculty of Medicine, İstanbul, Turkey
|Kara B, Karaman B, Özmen M, Rosti RÖ, Çalışkan M, Kayserili
H, Başaran S. Angelman syndrome: clinical findings and follow-up data of
14 patients. Turk J Pediatr 2008; 50: 137-142.|
The diagnosis of Angelman syndrome (AS) is based on the clinical features,
behavior, EEG findings, and genetic abnormalities. The physical, clinical and
behavioral aspects appear to attributable to localized central nervous system
(CNS) dysfunction of the ubiquitin ligase gene, UBE3A, located at 15q11.2.
The features of AS frequently become apparent at 1-4 years of age, and the
average age at diagnosis is 6 years.
Angelman syndrome was considered in the differential diagnosis of 30
patients who were referred to the Medical Genetics Department of İstanbul
Medical Faculty between 1995 and 2005. The diagnosis was confirmed in 14
patients (8 female, 6 male) by detecting the presence of deletion through
the use of fluorescence in situ hybridization (FISH) technique in all, while
high-resolution banding technique (HRBT) detected only seven of the
deletions. The patients’ ages at the time of diagnosis ranged from 2 to 12
(mean 4.10±2.59) years.
We report here on 14 patients with definite diagnosis of AS who displayed
the characteristic clinical features of the syndrome and additional findings
not previously reported, along with the follow-up data concerning neuromotor
development and seizures.
Angelman syndrome, dysmorphism, epilepsy, mental retardation, behavioral abnormalities
|Angelman syndrome (AS) is a neurogenetic
syndrome affecting children[1,2]. It was first
described in 1965 by Harry Angelman, an
English pediatrician. The prevalence of AS is
estimated to be around 1/10,000-1/20,000, and
among individuals with severe developmental
delay, as 0%, 1.3%, 1.4%, and 4.8%, in different
studies[1-4]. AS is characterized by severe mental
retardation, inappropriate laughter, happy
mood, ataxic gait, jerky/puppet-like movements
and minimal or absent speech. Dysmorphic
craniofacial features tend to become more
prominent with age and include postnatal onset
micro-brachycephaly, mid-facial hypoplasia,
deep-set eyes, macrostomia and prominent
mandible. Epileptic seizures occur in about
80% of patients.The EEG is usually more
abnormal than clinically expected, but it can
also be normal in individuals with genetically proven AS1. AS is a clinical diagnosis that can
be confirmed by genetic testing in about 80-
85% of the cases. The physical, clinical and
behavioral aspects appear to be attributable
to localized central nervous system (CNS)
dysfunction of the ubiquitin ligase gene,
UBE3A, located at 15q11.2.|
We report here on 14 patients with definite
diagnosis of AS who displayed the characteristic
clinical features of the syndrome and additional
findings not previously reported, along with
the follow-up data concerning neuromotor
development and seizures.
|Material and Methods |
|Thirty patients were referred to the Medical
Genetics Department of İstanbul Medical Faculty
between 1995 and 2005 due to unidentified etiology of severe mental retardation, severe
speech deficit, dysmorphic features, and
epileptic seizures or abnormal EEG findings,
and AS was suspected in the differential
diagnosis. All patients were evaluated by a
clinical geneticist. Metabolic screening tests
were performed in all and cranial magnetic
resonance imaging (MRI) in 29.|
Cytogenetic analysis was performed by highresolution
banding technique (HRBT) using
thymidine on all of the patients’ blood
lymphocytes. Twenty metaphases were
analyzed for each individual. Fluorescent
in situ hybridization (FISH) studies were
carried out with SNRPN probe (Cytocell).
Hybridization and application were performed
according to the manufacturers’ protocols.
DAPI (4’, 6-diamidino-2-phenyl-indole), FITC,
and Rhodamine fluorescence signals were
detected using specific filter combinations
(Pinkel #1, Chroma Technology).
|The diagnosis of AS was confirmed in 14
patients (8 female, 6 male) who had preliminary
diagnosis of AS by detecting the presence of
deletion through the use of FISH technique
in all, while HRBT detected only seven of
the deletions (Table I). The patients’ ages
at the time of diagnosis ranged from 2 to 12 years (mean 4.10±2.59 years). Gender, age,
age and head circumference at diagnosis, and
cytogenetic analysis (HRBT and FISH) results
of patients are shown in Table I. All patients
showed severe developmental delay, severe
speech deficit or absent speech, movement and
gait problems and behavioral abnormalities. Six
of them (42.8%) were ambulatory, 2 (15%)
could walk with support, and 6 could not
walk; 11 of them (78.5%) had absence of
speech, and 2 (14.2%) were able to speak a
few meaningful words. The gross motor and
language development of the patients are
summarized in Table I. Dysmorphic facial
features, neurologic and behavioral abnormalities
and pathologic EEG findings consistent with
the diagnosis of AS according to the criteria of
Williams et al. are shown in Table II. Additional
clinical findings observed in our patients are
summarized in Table III. Dysplastic and/or
simple ear and helical abnormalities (42.8%),
clinodactyly (35.7%), flat philtrum (35.7%),
pes equinovarus deformity (21.4%), midfacial
hypoplasia (21.4%), retro-micrognathia (21.4%),
narrow high-arched palate (28.5%) and finger
pads (28.5%) were the frequently associated
physical findings in our group of patients.|
| ||Table I: Gender, Age, Age and Head Circumference at Diagnosis, Time of Gross Motor and Speech
Development, and Cytogenetic Analysis (HRBT and FISH) Results of 14 Patients with Angelman Syndrome|
| ||Table II: Frequency of Features in our Series According to Angelman Syndrome
Diagnostic Criteria of Williams et al. (1995)|
| ||Table III: Frequency of Additional Anomalies Observed in our Series Not Listed
in the Consensus Criteria (Williams et al.)|
All patients had seizures and were on antiepileptic
therapy. Seizures were completely controlled in
4 patients, and partially controlled in 10. The onset of seizures, seizure type at onset, seizurefree
period at follow-up, age at last seizure, and
the recent antiepileptic therapy administered are
summarized in Table IV.
| ||Table IV: Onset of Seizures, Seizure Type at Onset, Seizure–Free Period at Follow–Up, Age at Last Seizure, EEG Abnormalities at Diagnosis, and
Recent Antiepileptic Therapy in 14 Patients with Angelman Syndrome|
Cranial MRI findings were normal in 11 patients
and in 2 showed minimal cerebral atrophy.
Cranial imaging was not performed in 1 patient.
Metabolic screening tests revealed normal results
in all patients. Family history was uneventful
except for one with an epilepsy history.
|Angelman syndrome (AS) is a geneticallydetermined
developmental disorder caused
by deletion of the maternally inherited
chromosome 15q11-13 (75% of cases), paternal
uniparental chromosome 15 disomy (2-3%
of cases), methylation imprinting mutation
(2-3% of cases), and UBE3A mutation
(2-3% of cases). In the remaining 15-20%
of patients, the genetic mechanism is still
unknown. DNA methylation testing is a reliable
screening test for deletions, uniparental disomy
(UPD) or imprinting center (IC) defects, but
it does not distinguish which of the three
mechanisms is operative[1,4]. To determine
the underlying mechanism, the next step is
to perform chromosome 15 FISH analysis to
detect 15q11.2-15q13 deletions. If there is no
deletion, additional genetic testing is necessary
to determine if either UPD or IC defects are
present. If the initial DNA methylation test is
normal, UBE3A mutations may be the possible
genetic mechanism, since these mutations have
no effect on the DNA methylation pattern of
the 15q11.2-15q13 region. Even though UBE3A
mutation testing reveals normal results, the
remaining group of patients could still be
affected by AS, thus belonging to 10-15% of
cases with unidentified etiology. In our series,
the diagnosis of AS was confirmed by only
HRBT and FISH in 14 of 30 (47%) patients
with the clinical characteristics of AS. It would
well be possible that the number of AS patients
may increase if the other three known genetic
mechanisms operative for AS had been tested
in our remaining 16 patients.|
UBE3A was identified as the AS gene, located
within the 15q11-13 region, in 1997 by two
different groups[8,9]. It produces a protein called
the E6-associated protein (E6AP), which acts
as a cellular ubiquitin ligase enzyme. In certain regions of the normal brain, UBE3A
is expressed only from the maternal allele and
its expression in the AS brain with 15q11.1-
15q13 deletion is only about 10% that of
normal. This phenomenon of monoallelic
or single chromosome regional expression
is termed genomic imprinting, and AS is a
typical example[1,11]. There is limited correlation
between the clinical severity of AS and its
type of genetic mechanism. Individuals with
the large chromosome deletions are more
likely to have seizures and microcephaly and
are more likely to have skin, eye, and hair
hypopigmentation. Those with uniparental
disomy are more likely to have no seizures,
normal head circumference, and better cognitive
functioning, although severe to profound
impairment is still present. Those with UBE3A
and IC defects are more likely to have moderate
clinical severity between the former and latter
mechanisms stated above. Chromosomal
deletion was the only genetic mechanism
detected in our patients, and as such, when
evaluating the clinical features of our patients,
they should be compared only with the deleted
AS cases reported previously.
Severe speech deficit, severe mental retardation,
behavioral abnormalities and movement
problems are ubiquitous in AS, while other
features, such as microcephaly or seizures,
may be absent. The diagnosis of AS is
primarily clinical and can be confirmed by
laboratory tests. However, its diagnosis
remains difficult in infants who do not present
the typical features. If the child is less than
12 months of age, tremulous movements,
ataxia or severe lack of speech may not be
apparent, and likewise seizures may not have
occurred yet1. The facial features and physical
examination may generally appear normal,
and development during the first six months
of life is not apparently delayed, although
protruding tongue, strabismus, brisk deep
tendon reflexes and apparent happy demeanor
may be present in this period. As the child
with AS grows, the definite diagnosis may be
possible with speech being essentially absent
and gait anomalies becoming evident due to
severe jerkiness and ataxia. Typical dysmorphic
features evolve over the first five years. They
are socially outgoing, quite hyper-motoric
and are moving forward developmentally.
Pediatricians often first encounter AS while consulting on an infant with the problem of
developmental delay, microcephaly or seizures.
AS should be on the differential diagnosis list
of any child with microcephaly, seizures, typical
behavioral problems and gait abnormalities. In
our group of patients, age at diagnosis was
4.10±2.59 years, some two years earlier than
reported data. Early confirmed diagnosis of AS
can help to avoid unnecessary investigations.
Family planning issues can also be discussed
more in advance.
A consensus for diagnostic criteria was
established in 1995, and updated in 2005 by
Williams et al.. They appear indicative in
clinical practice even if the diagnosis can not be
excluded when they are not uniformly present.
There are three parts of the consensus criteria.
All the features of part A are consistent with
AS; thus, patients should have all of these
features for the diagnosis of AS. Features of part
B and part C are not necessary for the diagnosis.
Features of part C contain many minor physical
abnormalities, sleep disturbance and attraction
to water. In our series, we observed some
physical findings not listed in the consensus
criteria. Dysplastic and/or simple ear and
helix abnormalities, clinodactyly, midfacial
hypoplasia, retro-micrognathia, flat philtrum,
finger pads and pes equinovarus deformity were
the frequently associated minor anomalies in
our series. These new findings may be included
in part C of the consensus criteria, if further
studies support our findings.
The prevalence of EEG abnormalities is about
80% in AS patients. EEG abnormalities are
much more prominent in AS patients with
a deletion (97-100%), although normal EEG
background activity was reported in 72.2%
of AS patients with UPD, IC defects and
UBE3A mutations[16,17]. EEG abnormalities were
observed in all our AS patients.
The prevalence of epilepsy is 80-90% in
AS patients[1,2,4]. The age at seizure onset is
usually between 1 and 2 years, but seizures
can occur in infants less than 1 year old or
older than 3 years2. Seizures may be difficult
to control, especially in early childhood, and
may decrease or cease by the time the patient
is in their mid-teens or early adulthood[2,4].
However, some authors report good control
with classic antiepileptic drugs for generalized
and partial seizures, but not in non-convulsive status epilepticus and atypical absences[5,14].
The most effective antiepileptic drugs are
valproate in combination with clonazepam or
other benzodiazepines, whereas carbamazepine
sometimes has an adverse effect. Experience
with new antiepileptic drugs is limited. All of
our patients had a history of epileptic seizures.
Epileptic seizures were under complete control
in 4 patients and partial control in 10 patients
with classic antiepileptic drugs.
In conclusion, the prevalence of AS in patients
with severe mental retardation, speech deficit
and epilepsy is not rare. In infants with
typical EEG findings, developmental delay
and behavioral abnormalities, with or without
seizures, the diagnosis of AS should be
considered and genetic testing performed.
Early diagnosis of the syndrome is important
for genetic counseling, early therapeutic
intervention of epileptic seizures, especially
nonconvulsive status epilepticus, and avoidance
of over-treatment for EEG abnormalities[5,14].
1. Williams CA. Neurological aspects of the Angelman
syndrome. Brain Dev 2005; 27: 88-94.
2. Rubin DI, Patterson MC, Westmoreland BF, Klass DW.
Angelman’s syndrome: clinical and electroencephalographic
findings. Electroenceph Clin Neurophysiol 1997;
3. Angelman H. Puppet children: a report on three cases.
Dev Med Child Neurol 1965; 7: 681-688.
4. Laan L, Haeringen A, Brouwer OF. Angelman syndrome:
a review of clinical and genetic aspects. Clin Neurol
Neurosurg 1999; 101: 161-170.
5. Buoni S, Grosso S, Pucci L, Fois A. Diagnosis of
Angelman syndrome: clinical and EEG criteria. Brain
Dev 1999; 21: 296-302.
6. Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman
syndrome 2005: updated consensus for diagnostic criteria.
Am J Med Genet 2006; 140: 413-418.
7. Miano S, Bruni O, Leuzzi V, Elia M, Verrillo E, Ferri
R. Sleep polygraphy in Angelman syndrome. Clin
Neurophysiol 2004; 115: 938-945.
8. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP
mutations cause Angelman syndrome. Nat Genet 1997;
9. Matsuura T, Sutcliffe JS, Fang P, et al. De novo
truncating mutations in E6-AP ubiquitin-protein ligase
gene (UBE3A) in Angelman syndrome. Nat Genet
1997; 15: 74-77.
10. Rougeulle C, Glatt H, Lalande M. The Angelman
syndrome candidate gene, UBE3A/E6-AP, is imprinted
in brain. Nat Genet 1997; 17: 14-15.
11. Jiang Y, Tsai TF, Bressler J, Beaudet AL. Imprinting
in Angelman and Prader-Willi syndromes. Curr Op
Genet Develop 1998; 8: 334-342.
12. Wang PJ, Hou JW, Sue WC, Lee WT. Electroclinical
characteristics of seizures- comparing Prader-Willi
syndrome with Angelman syndrome. Brain Dev 2005;
13. Hou JW, Wang PJ, Wang TR. Angelman syndrome
assessed by neurological and molecular cytogenetic
investigations. Pediatr Neurol 1997; 16: 17-22.
14. Ohtsuka Y, Kobayashi K, Yoshinaga H, et al. Relationship
between severity of epilepsy and developmental outcome
in Angelman syndrome. Brain Dev 2005; 27: 95-100.
15. Laan LA, Vein AA. Angelman syndrome: is there a
characteristic EEG? Brain Dev 2005; 27: 80-87.
16. Laan LA, Renier WO, Arts WF, et al. Evolution of
epilepsy and EEG findings in Angelman syndrome.
Epilepsia 1997; 38: 195-199.
17. Minassian BA, DeLorey TM, Olsen RW, et al. Angelman
syndrome: correlations between epilepsy phenotypes
and genotypes. Ann Neurol 1998; 43: 485-493.
[Mail to Editor ]