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 but those with int dup(15) have only one extra copy resulting in milder symptoms than idic(15). 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.
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. The seizure rate for those with idic(15) was much higher as 63% had seizures. The seizure severity was also generally increased in idic(15) compared to int(15). Out of those with idic(15) and seizures, 81% had multiple seizure types. The most common seizure type was generalized tonic-clonic (60% - also called “grand mal” seizures and consist of loss of consciousness with shaking of arms and legs). Other common seizure types were atonic (40% - these are brief head drops or drops to the floor), myoclonic (40% - very quick “lightning-like jerks”), focal onset (40% - seizures that start on one side of the body or face), tonic (38% - presents as stiffening) and absence (31% - presents as staring spells).
Active seizures (which are defined as having a seizure in the past year) may increase with age. The rate of active seizures was 14% in children under 3, compared to 68% in those over 18 years old. With puberty, 65% of respondents experienced a worsening of seizures, 18% had improvement and 18% had no significant changes. This may not accurately represent the rate of seizures in adolescents/young adults as there were not many included in the survey. Status epilepticus (prolonged seizure lasting more than 15 minutes) was reported in 33% of respondents and 67% reported at least one hospitalization due to seizures. Developmental regressions were reported in 63% respondents, with 61% of those attributing these episodes of regression to frequent or prolonged seizure activity.
Of note, 42% of those who had seizures in idic(15) reported a history of a specific type of seizure called infantile spasms. Infantile spasms usually begin in the first year of life. They are often characterized by a sudden bending forward of the body with stiffening of the arms and legs and may occur in clusters. Some children will arch their backs as they extend their arms and legs. Infantile spasms tend to occur after awakening or feeding. The average age of onset was 6-7 months and the average duration the spasms lasted was nearly 1 year. Spasms typically resolved before 3 years of age.
Infantile spasms were the first seizure type for all 22 individuals who had them. Afterwards, 91% of them went on to develop other seizure types, including tonic (58%), atonic (46%), myoclonic (42%) and atypical absence (42%).
The 2 most common treatments for the 22 children with infantile spasms were ACTH/prednisone and vigabatrin. The only other medications used by more than one respondent were valproic acid and topiramate. ACTH/prednisone was significantly more effective than vigabatrin in controlling seizures (75% for ACTH/prednisone vs 29% for vigabatrin).
Epilepsy in those individuals with idic(15) often does not respond to medication. Only 24% of the respondents reported a >90% seizure reduction from the first medication, sustained over a period of at least 1 year. An additional 21% showed a 50-90% seizure improvement, sustained over 1 year with the first medication. For the second medication prescribed, there was a 36% response rate.
The most commonly prescribed medications were valproic acid (Depakote - 60%), levetiracetam (Keppra - 44%), lamotrigine (Lamictal - 37%), carbamazepine (Tegretol - 35%), zonisamide (Zonegran - 23%) and clonazepam (Klonopin - 23%).
Family members were asked which medications they thought were most effective at controlling seizures. Rufinamide (Banzel - 67%) was thought to be most effective, followed by carbamazepine (Tegretol - 44%), lamotrigine (Lamictal - 37%), oxcarbazepine (Trileptal - 33%) and valproic acid (Depakote - 32%). Less than 5% of those asked thought that benzodiazepenes (such as clonazepam) were an effective treatment for seizures.
At the time of the study, the percentage of people who were still taking the medication was highest in rufinamide (100%), followed by lamotrigine (53%), valproic acid (45%) and zonisamide (42%). Intolerable side effects were most common in levetiracetam (Keppra - 52%, behavioral), zonisamide (Zonegran - 50%, sedation), clobazam (Onfi - 50%, sedation), oxcarbazepine (Trileptal - 50%, sedation) and topiramate (Topamax - 48%, sedation).
Only a few respondents had family members who tried non-medication treatments, such as ketogenic diet, vagus nerve stimulation, gluten-free diet and surgical resection. Not enough data were available to make any conclusions about effectiveness or tolerability of these treatments.
This is the largest study to date examining epilepsy and its treatments in Dup15q syndrome. Epilepsy is common in idic(15) with a high prevalence of infantile spasms and is typically resistant to medication. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. For infantile spasms, ATCH/prednisone treatment appears to be much more effective than vigabitran. For other seizure types, Banzel, Tegretol, Lamictal, Trileptal and Depakote were reported as the most effective medications but the study is not large enough to say this definitively. In general, it appears that GABAergic medications, such as benzodiazepenes and vigabitran, may not be effective in treating seizures. This may be related to the duplicated GABA receptors in dup15q. This study did have some limitations because it was a questionnaire based-study which relied on family reporting and was subject to more responses from families dealing with more difficult seizures. Hopefully, larger studies will available in the future to gain a better understanding of epilepsy in dup15q syndrome and ultimately lead to better approaches to effective treatment.