Chromosome 15q11.2-13.1 duplication syndrome (dup15q) is a clinically identifiable syndrome which results from duplications of chromosome 15q11.2-13.1. These duplications most commonly occur in one of two forms, either an extra isodicentric 15 chromosome, abbreviated idic(15), or an interstitial duplication 15, abbreviated int dup(15). Those with idic(15) have 2 extra copies of the duplicated region and those with int dup(15) have one extra copy. There is a wide range in the severity of characteristics found in dup15q syndrome. However, common characteristics often include developmental delay, seizures [in idic(15)], hypotonia, intellectual disability, absent or poor language, and autistic behavior. People with int dup(15) usually tend to have milder findings than those with idic(15) since they have one fewer copy.
Approximately 400 families were contacted through the Dup15q Alliance and asked to complete a questionnaire survey online regarding the presence and presentation of epilepsy in their family member with a chromosome 15q duplication. There were responses from 95 family members of individuals with chromosome 15q duplications, representing a response rate of ~25% of the entire Dup15q Alliance in 2009. There were 12 individuals (5 male, 7 female) with int dup(15) and the remaining 83 had some variation of a marker idic(15) chromosome.
For those with int dup(15), only 3 (25%) of 12 had seizures with one of the three reporting only a single seizure. This seizure rate is similar to that reported in the autistic spectrum population in general. For those with idic(15), 52 (63%) of 83 had seizures, 81% of those with seizures having multiple seizure types. The most common seizure type was generalized tonic-clonic (60% of those with seizures), with high rates of other seizure types typically present in Lennox-Gastaut syndrome (LGS) including atonic (40%), myoclonic (40%), focal onset (40%), tonic (38%) and absence (31%). Those with idic(15) also had more severe epilepsy phenotypes with mean Early Childhood Epilepsy Severity Scale (EChess) scores more than double those with int dup(15).
Active seizures (non-spasms), as defined by those with seizures in the past year, increased in nearly every age group from <3 years(14%) to 18 years (68%). Active seizures were most prevalent in those 15-17 years (67%) and 18+ years (68%), but there were relatively few respondents for those 15+ years so these results may be affected by response bias.
Of note, 42% of those who had seizures in idic(15) reported a history of infantile spasms. Infantile spasms were the first seizure type for all 22 individuals who had them with 20 (91%) developing subsequent seizure types. The epilepsy phenotype in idic(15) often begins as infantile spasms, evolving into an LGS-type picture with multiple generalized seizure types, including tonic (58%), atonic (46%), myoclonic (42%) and atypical absence (42%). Spasms typically resolved before 3 years of age, as the average age of onset was 6-7 months with an average duration of nearly 1 year.
For the 22 children with infantile spasms, the most common first and second medications used were adrenocorticotropic hormone (ACTH)/prednisone (5, first; 7, second) and vigabatrin (VGB; 5, first; 2, second), with the only other medications used by more than one respondent being valproic acid (VPA, 2) and topiramate (TPM, 2). ACTH/prednisone was significantly more effective than VGB in controlling seizures (75% vs. 29% with >90% seizure reduction for those that tried each medication) with similar rates of seizure exacerbation.
Parental reporting indicates that epilepsy (non-spasms) in idic(15) is refractory to medication, as there was only a 24% response rate (defined as >90% seizure reduction sustained for at least 1 year) to the first medication prescribed with an additional 21% showing a 50-90% seizure improvement. For the second medication prescribed (N=25), there was a 36% response rate.
The most commonly prescribed medications were VPA (60%), levetiracetam (LEV 44%), TPM (40%), lamotrigine (LTG 37%), carbamazepine (CBZ 35%), zonisamide (ZNS, 23%) and clonazepam (CLZ 23%). Family members believed that the most effective medications for controlling seizures were the following: rufinamide (RUF; 67%, N=6), CBZ (44%, N=18), LTG (37%, N=19), oxcarbazepine (OXC; 33%, N=6), and VPA (32%, N=31). Overall, only 1 (<5%) of 22 of those who tried a typical benzodiazepine indicated that it was the most effective medication.
The percentage of those still taking each medication at the time of the study was highest in the broad spectrum AED, such as RUF (100%, N=6), LTG (53%, N=19), VPA (45%, N=31), and ZNS (42%, N=12). Intolerable adverse effects were reported most frequently in those taking LEV (52%, most common behavioral), ZNS (50%, sedation), clobazam (CLB; 50%, sedation), OXC (50%, sedation) and TPM (48%, sedation).
Only a few respondents had family members who tried nonpharmcologic treatments, such as the ketogenic diet (N=1), vagus nerve stimulation (N=7), gluten free diet (N=1) and surgical resection (N=1). Not enough data were available to allow an adequate analysis of efficacy or tolerability of these treatments.
Epilepsy is common in idic(15) with a high prevalence of infantile spasms and is typically refractory to medication. Although the epilepsy phenotype in idic(15) appears to be most consistent with a LGS-type of epilepsy and responds best to broad spectrum AED, the seizures also respond well to CBZ, which typically exacerbates LGS, suggesting that these epilepsies may be more multifocal than generalized. These seizures did not respond well to typical benzodiazepines, with lower response rates and relatively higher rates of seizure exacerbation, although CLB, an atypical benzodiazepene, was relatively effective and had no reported seizure exacerbations. This study suggests that GABAergic medications, such as typical benzodiazepenes and vigabitran, may have a relative lack of efficacy in dup15q syndrome. It is possible this is due to abnormal GABAergic transmission resulting from the duplication of a cluster of GABA beta3 receptor genes in the 15q11.2-13 region. Seizures in those with int dup(15) are less common, likely due to one duplicated copy as opposed to 2 copies in idic(15), with a frequency similar to the general autism spectrum population. Although this is the largest study to date assessing epilepsy in this population, the results may be susceptible to bias since it was a questionnaire-based study. Larger studies, ideally prospective studies, would be necessary to make definitive determinations regarding the treatment of seizures in this population.