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.

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.

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).

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.

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[1]. 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[10]. 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[1]. 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[1]. 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[1]. The diagnosis of AS is primarily clinical and can be confirmed by laboratory tests[12]. However, its diagnosis remains difficult in infants who do not present the typical features[13]. 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[14]. 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[1]. Typical dysmorphic features evolve over the first five years[4]. They are socially outgoing, quite hyper-motoric and are moving forward developmentally[1]. 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.[6]. They appear indicative in clinical practice even if the diagnosis can not be excluded when they are not uniformly present[5]. 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[15]. 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[4]. 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].