Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk?

Abstract

Background: Autism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families.

Methods: We extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven's Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS).

Results: The prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4).

Conclusions: Epilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.

Figure 1

Distribution of age of first seizure, age of individuals with ASD and epilepsy, and age of individuals with ASD without epilepsy. Age of first seizure (n = 55, black), age of individuals with ASD and epilepsy (n = 61, green or grey), and age of individuals with ASD without epilepsy (n = 417, white and blue). ASD, autism spectrum disorders.

Figure 2

Theoretical distribution of ages of onset of seizures for 55 individuals with comorbid multiplex autism with epilepsy. Distribution shows two subgroups with early onset of seizures (mean = 2.3 years (± 1.3)) and late onset of seizures (mean = 8.3 years (± 3.5)). A parametric bootstrap with B = 500 replications of the likelihood ratio statistic was performed for testing the null hypothesis of a one-component fit versus the alternative hypothesis of a two-component fit. The result was significant (P = 0) and therefore the model with two components was adequate.

Figure 3

Frequencies of comorbid epilepsy in children (n = 386) with autism from multiplex families as function of the Vineland Adaptive Behavior Scales (VABS) composite standard score.