The aim of this study was to investigate the natural history of epilepsy and response to anti-epileptic drug treatment in patients with Angelman syndrome (AS) in Korea.
We retrospectively reviewed the clinical records of 14 patients diagnosed with epilepsy out of a total of 17 patients with a genetic diagnosis of AS. These patients were seen at the Department of Pediatric Neurology at Severance Children's Hospital from March 2005 to March 2011.
Fourteen (9 males and 5 females) subjects (82.3%) were diagnosed with epilepsy in AS. The most common seizure types were generalized tonic-clonic (n=9, 27%) and myoclonic (n=9, 27%), followed by atonic (n=8, 24%), atypical absence (n=4, 12%) and complex partial seizure (n=3, 9%). The most commonly prescribed antiepileptic drug (AED) was valproic acid (VPA, n=12, 86%), followed by lamotrigine (LTG, n=9, 64%), and topiramate (n=8, 57%). According to questionnaires that determined whether each AED was efficacious or not, VPA had the highest response rate and LTG was associated with the highest rate of seizure exacerbation. Complete control of seizures was achieved in 6 patients. Partial control was achieved in 7 patients, while one patient was not controlled.
Epilepsy is observed in the great majority of AS patients. It may have early onset and is often refractory to treatment. There are few reports about epilepsy in AS in Korea. This study will be helpful in understanding epilepsy in AS in Korea.
Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retraction, speech disorder, stereotyped jerky movement and an overall happy disposition accompanied with frequent laughter
About 90% of these patients have epileptic seizures
There are only a few reports about epilepsy in patients with AS in Korea
We retrospectively reviewed the clinical records of 14 patients (82.3%) with epilepsy out of 17 patients that had been given the genetic diagnosis of AS, who visited Severance Children's Hospital from March 2005 to March 2011. The genetic study was carried out using an analysis of the methylation pattern of the 15q11-13 region of chromosome 15 and fluorescence
Demographic data including age and gender were collected from medical records while clinical data including epilepsy were collected from questionnaires as well as from medical records. We studied the characteristics of the epilepsy, age of onset, frequency and type of seizures, and the type of treatment patients received. We also analyzed the characteristics of the electroencephalography (EEG) results initially and during follow-up.
Of the 17 patients (9 males and 8 females) with the genetic diagnosis of AS, 3 patients (18%) were determined by maternal deletion of chromosome 15q11-13 by FISH, but 14 patients (82%) were determined by abnormal methylation of maternal allele only, and further evaluation to identify the underlying mechanism (deletion, UPD, ID or
The mean age at diagnosis of AS was 6.5 years, with an age range between 1.4 years and 22.4 years. Twelve patients were diagnosed with epilepsy under 3 years of age (86%). In 2 patients over the age of three years presenting with epilepsy, the mean age of diagnosis of epilepsy was 3.6 years.
Age of seizure onset was a mean of 1.9 years (range, 7 months to 4.0 years). The most frequent types of initial seizure were GTC (n=4, 29%) and atonic (n=4, 29%), followed by myoclonic (n=3, 21%), complex partial seizure (n=2, 14%) and atypical absence (n=1, 7%) (
Ten patients were able to walk alone, whereas 4 patients were not. The mean age when the patients started walking was 3.8 years (range, 2 to 6.5 years). At the time of the study, patients had an average of 2.4 current antiepileptic drug (AED) medications, with 14% and 86% having tried monotherapy and multiple medications. The most commonly prescribed AED was valproic acid (VPA, n=12, 86%) followed by lamotrigine (LTG, n=9, 64%), topiramate (TPM, n=8, 57%), levetiracetam (LEV, n=5, 36%), zonisamide (ZNS, n=5, 36%), clonazepam (CLZ, n=2, 14%) and phenobarbital (Pb, n=2, 14%) (
In our series, the EEG patterns initially showed a typical AS pattern characterized by slow waves of high voltage in 71% (n=10) of patients. Normal EEG patterns were observed in 14% (n=2) of patients. Family members of the study subjects were asked whether each AED was efficacious or not in controlling the episodes of epilepsy. VPA (n=5, 36%) had the highest response rate of being efficacious, followed by TPM (n=3, 21%), LEV (n=2, 14%), and LTG (n=1, 7%). LTG (n=2, 14%) was associated with the highest rate of seizure exacerbation.
No patients tried non-pharmacologic therapies such as dietary therapy, vagal nerve stimulation or surgical intervention for their epilepsies. Complete control (seizure free more than a year) of seizures was achieved in 6 patients. Partial control (seizure more than once a year, but under once a month) was achieved in 7 patients, while 1 patient was not controlled (seizure more than once a month). Control of seizures was achieved at a mean age of 7.5 years (range, 3.6 to 14.1 years).
In more than 90% of patients with a clinical diagnosis of AS, genetic testing can demonstrate a molecular mechanism that causes lack of expression of the
Epileptic seizures occur in 80% of patients that have AS
The percentage of those with multiple seizure types (71%) was somewhat higher what has been described in previous reports
Ten patients were able to walk alone (group A), whereas 4 patients were not. The mean age at which the patients started walking was 3.8 years (range, 2 to 6.5 years). Although four patients were older than the mean age of walking, two patients (group B, 4.6 years and 4.4 years) had a higher probability to walk alone in comparison with the other two patients (group C, 12.9 years and 10 years) because they were younger than the age to walk alone of the latest patient (6.5 years). Group C showed the worst seizure control as uncontrol and partial control in each patient. Group B showed better seizure control than group C as partial controls in all 2 patients. Group A showed best seizure control as complete control in 6 patients, and partial control in 4 patients. There are reports that the deletion phenotype is generally linked to a more severe clinical picture in that 95% of patients manifest more severe seizure patterns and mental retardation
Epilepsy in AS appears to improve around puberty
There are specific EEG patterns in AS patients which appear in isolation or in different combinations. They are similar in patients both with and without seizures. In childhood, the three characteristic patterns are 1) persistent rhythmic 4 to 6 Hz activity, 2) prolonged runs of rhythmic triphasic 2 to 3 Hz activity, maximal over the frontal regions and normally mixed with spikes or sharp waves, and 3) spikes mixed with 3 to 4 Hz component, mainly posteriorly and facilitated by eye closure
Earlier reports suggested a decreasing frequency of epileptic seizures with age
Many AEDs are used to treat seizures in individuals with AS, but there is no agreement on optimal seizure medication, although VPA, LTG, TPM, LEV, and CLZ are more commonly used
Some children with uncontrollable seizures have been placed on a ketogenic diet, and occasionally vagal nerve stimulation has been used. As reported by Thibert et al.
The limitation of this study was that a more precise genetic subtype of each patient was not evaluated. Lossie et al.
In conclusion, epilepsy is very common in AS and typically refractory to medication. Our study will be helpful in understanding epilepsy in AS patients in Korea. Further characterization of epilepsy in AS along with advances in genetic analyses will hopefully lead to a better understanding of the pathogenesis of epilepsy in AS. Further studies with a larger population on effective treatment of epilepsy in AS and improvements in the management of problems such as behavior, communication, learning, motor impairment, and sleep disturbances in AS are also needed.
This work was supported by National Research Foundation grant funded by the Korea government (MEST) (2010-0020353).
The types of initial seizure and during follow-up period. (A) Initial seizure type. (B) Sezure type during follow-up. AA, atypical absence seizure; AT, atonic seizure; CPS, complex partial seizure; GTC, generalized tonic-clonic seizure; Mcl, myoclonic seizure.
Clinical Characteristics in Patients with Angelman Syndrome
SE, status epilepticus; EEG, electroencephalography.
*Partial controlled, more than once a year but under than once a month. †Seizure free, seizure free more than a year. ‡Uncontrolled, more than once a month.
History of Antiepileptic Drugs (AEDs) Treatment in Angelman Syndrome
Values are presented as number (%).