Absence Seizures with Intellectual Disability as a phenotype of the 15q13.3 microdeletion syndrome

SUMMARY

15q13.3 microdeletions are the most common genetic findings in Idiopathic Generalized Epilepsies identified to date, present in up to 1% of patients. In addition, 15q13.3 microdeletions have been described in patients with epilepsy as part of a complex neurodevelopmental phenotype. We analyzed a cohort of 570 patients with various pediatric epilepsies for 15q13.3 microdeletions. Screening was performed using quantitative polymerase chain reaction, deletions were confirmed by array comparative genomic hybridization. We carried out detailed phenotyping of deletion carriers. In total, we identified four pediatric patients with 15q13.3 microdeletions including one previously described patient. 2/4 deletions were de novo, 1 deletion was inherited from an unaffected parent, and in one patient, inheritance is unknown. All four patients had absence epilepsy with various degrees of intellectual disability. We suggest that absence epilepsy accompanied by intellectual disability may represent a common phenotype of the 15q13.3 microdeletion in pediatric epilepsy patients.

INTRODUCTION

Structural genomic variations are increasingly recognized as genetic risk factors for various epilepsies (Mefford et al. 2010). Amongst the different microdeletions described to date, 15q13.3 stands out as the most common genetic risk factor for epilepsy. Specifically, 15q13.3 microdeletions are found in up to 1% of patients with Idiopathic Generalized Epilepsy (IGE) (Dibbens, et al. 2009, Helbig, et al. 2009), but have also been described in other types of seizure disorders. While 15q13.3 also predispose to a wide spectrum of other neurodevelopmental disorders including intellectual disability, autism and schizophrenia (Sharp, et al. 2008, Stefansson, et al. 2008, van Bon, et al. 2009), epilepsy appears to be a frequent feature in deletion carriers.

Given the broad phenotype associated with 15q13.3 microdeletions, we screened a pediatric epilepsy cohort including patients with various degrees of intellectual disability for 15q13.3 microdeletions.

METHODS

Clinical Analysis

A cohort of 570 children and adolescents with various epilepsy subtypes, febrile seizures and epilepsy-related EEG features (Supplemental Table 1) were included and iterative phenotyping (Manolio, et al. 2009) was performed in individuals with identified deletions. The majority of patients were of Caucasian descent. None of the 570 patients has been included in previous studies (Helbig, et al. 2009, Mefford et al. 2010). Due to the phenotypic features, one previously described patient (Helbig, et al. 2009; ID 1674) was included. This patient was not included in the statistical analysis.

Detailed phenotypic analysis and review of multiple EEGs was performed in 3/4 patients. Phenotyping was carried out in family members if available; the family of proband 3 was lost for follow-up. Epileptic syndromes were described according to the classifications of the International League against Epilepsy (Engel 2001). Written informed consent was obtained by participants or parents in case of minors. The study was approved by the local ethics.

Genetic Analysis

Screening of the cohort for 15q13.3 microdeletions was performed using quantitative PCR (TaqMan®, Applied Biosystems) with intronic probes for the second intron of CHRNA7. Confirmation of 15q13.3 microdeletions and refining of the breakpoints in probands and screening of family members was performed using high-resolution custom array comparative genomic hybridization with 4398 probes in the 15q13 BP3-BP5 region (hg18, chr15:26,500,000–31,000,000; average probe spacing 1250bp; Agilent Technologies, Santa Clara, CA).

RESULTS

In a cohort of 570 pediatric patients, we identified three individuals with a 15q13.3 microdeletion. All three individuals as well as a previously described patient presented with various degrees of intellectual disability and absence epilepsy. Dysmorphic features were not present. Clinical characteristics of the probands and their families are summarized in Supplemental Tables 1 and 2.

The 15q13.3 microdeletion was exclusively found in patients with generalized epilepsies (3/101 IGE patients) compared to the remaining pediatric patients predominantly with focal epilepsies and febrile seizures related syndromes (0/469). This difference was statistically significant (p = 0.006). Also, the microdeletion was exclusively present in patients with absence seizures (3/31 vs. 0/539; p = 0.0002). None of the deletion carriers had additional chromosomal rearrangements.

Proband 1

The girl was born at term to non-consanguineous healthy parents of Northern European ancestry. Birth parameters, postnatal period and acquisition of motor skills were normal, cognitive and language development was delayed.

At the age of five, she presented with severe intellectual disability, autistic features and typical absence seizures. The EEG showed paroxysms of regular 3Hz generalized spike-wave lasting for up to 15 seconds, accompanied by clinical absences (Figure 1A). Seizures were controlled on ethosuximide, which was withdrawn at the age of eight. Relapse of absence seizures occurred in puberty, again responsive to ethosuximide. At the age of 14, EEG recordings showed photosensitivity, at the age of 19, the EEG and MRI were normal.

Figure 1. EEG recordings of 15q13.3 microdeletion carriers.

(A) Bilateral synchronous regular 3 Hz spike-wave discharges in proband 1 lasting for 15 seconds associated by clinical absence seizures. (B) Absence seizure in proband 2 lasting for 4 seconds. (C) Spike-wave discharges lasting for three seconds in proband 4. This proband was affected by absence status lasting for more than 6 hours.

Her brother presented with severe intellectual disability, but not epilepsy. Both parents and a second brother were unaffected (Figure 2). The EEG of the mother (unaffected deletion carrier) showed background slowing (7Hz) and no epileptic discharges. Microdeletions of 15q13.3 between breakpoints BP4 and BP5 were detected in the proband (Supplemental Figure 1), the brother with intellectual disability and the unaffected mother.

Figure 2. Pedigrees of 15q13.3 microdeletion carriers.

All four probands (marked by the arrow) are affected with absence seizures and intellectual disability. Additional microdeletion carriers (family of proband 1) are marked by an asterisk. No deletions (“no del”) were found in several relatives investigated by array-CGH.

Proband 2

The boy was born at term after an unremarkable pregnancy with normal birth parameters as the second child of non-consanguineous parents of Turkish ancestry. Early motor and cognitive development was unremarkable.

Frequent absence seizures were noted at the age of seven accompanied by regular generalized 3 Hz spike-wave discharges. Mild intellectual disability became obvious at the age of eight. Valproic acid therapy suppressed absence seizures which relapsed twice upon discontinuation at the age of 12 and 16 (Figure 1B). A single generalized tonic-clonic seizure occurred in the context of incompliance during adolescence. At the age of 24, occasional absences are reported. The proband has attended a school for intellectually disabled children and aggressive behavior is reported.

The proband’s brother (26 years) has moderate intellectual disability. The father had uncharacterized epileptic seizures in childhood with normal intellectual ability.

The proband’s sister (18 years) and mother are unaffected.

A de novo microdeletion of 15q13.3 was detected between breakpoints BP4 and BP5.

Proband 3

The boy is the only child of unrelated healthy parents of Northern European descent. Pregnancy, birth parameters and postnatal period were unremarkable.

The proband presented with rare typical absence seizures starting at the age of 13, consistent with Juvenile Absence Epilepsy. Seizures were controlled on ethosuximide. EEG recordings were not available and the family was lost for follow-up. The patient is attending a school for intellectually disabled children. Aggressive behavior was reported.

A maternal aunt was reported to have intellectual disability with unknown etiology.

A 15q13.3 microdeletion between breakpoints BP4 and BP5 was identified in the proband. Family members were not available for testing.

Proband 4

The girl was born at term as the sixth child to non-consanguineous parents of Northern European ancestry. Birth parameters and postnatal period were unremarkable. Gross and fine motor skill as well as language development was unremarkable in the first four years of life. Learning difficulties became obvious in childhood and the patient attended a school for intellectually disabled children.

At the age of 17, the proband presented with a single GTCS with subsequent stupor lasting for more than six hours. The EEG revealed continuous spike-wave discharges consistent with absence status, which was interrupted by i.v. clonazepam. In addition, the patient had brief 3Hz generalized spike-wave discharges (Figure 1C). MRI imaging revealed a small right occipital subependymal periventricular heterotopia (Supplemental Figure 2). The patient became seizure-free on lamotrigine and topiramate.

Family history is negative for seizures or intellectual disability. A de novo 15q13.3 microdeletion was identified in the proband.

DISCUSSION

In our study of a pediatric epilepsy cohort, we identified four patients altogether with 15q13.3 microdeletions presenting with absence seizures accompanied by intellectual disability. Some children with typical absence epilepsy may have learning disabilities (Titomanlio, et al. 2007, Wakamoto 2008), but the frequency of the combination of typical absence epilepsy and obvious intellectual disability is unknown. Interestingly, this combination of phenotypes was found in previous studies in 15q13.3 microdeletion carriers (Helbig, et al. 2009, Sharp, et al. 2008).

Given that our cohort consisted of unselected cases with pediatric epilepsies, the similarity of the phenotypes of 15q13.3 microdeletion carriers was surprising. All patients had absence seizures and various degrees of intellectual disability. The association of 15q13.3 microdeletions with absence epilepsy compared to other phenotypes seen in our cohort was statistically significant. The similarity of the phenotypes in our pediatric cohort is contrasted by the otherwise heterogeneous phenotypes associated with this microdeletion, including a broad spectrum of neuropsychiatric and neurologic disorders.

The phenotypes associated with the 15q13.3 microdeletion depend on the cohort investigated. Particularly, inclusion and exclusion criteria such as intellectual disability in epilepsy cohorts can influence the findings. For example, intellectual disability is a typical exclusion criterion for IGE, a common 15q13.3 microdeletion-related phenotype.

We suggest the following explanation for the similar phenotypes in our cohort: as the 15q13.3 microdeletion is known to increase risk for both absence epilepsy and intellectual disability, the frequency of this variant is likely to be increased in “overlap phenotypes”.

The variable phenotypic expression of the 15q13.3 microdeletion families 1–2 is intriguing. In family 1, the variant is inherited from an apparently unaffected mother. In family 2, the proband’s father is affected by epilepsy and the proband’s brother has intellectual disability. However, the variant is only present in the proband. Incomplete segregation and the existence of affected family members not carrying the variant has previously been observed in families with 15q13.3 microdeletions (Dibbens, et. al. 2009) and is as yet unexplained. Subtle unobserved neuropsychological phenotypes und apparently unaffected carriers and the existence of strong modifier genes in families might account for some of this variability.

CONCLUSION

Awareness of the associated phenotypes should alert clinicians to consider 15q13.3 microdeletions. Particularly the comorbidity of absence seizures and intellectual disability (ASID) should prompt screening for this particular chromosomal imbalance, which may represent a common constellation for the 15q13.3 microdeletion in pediatric epilepsy patients.