Somatic overgrowth predisposes to seizures in autism spectrum disorders

Abstract

Background: Comorbidity of Autism Spectrum Disorders with seizures or abnormal EEG (Autism-Epilepsy Phenotype) suggests shared pathomechanisms, and might be a starting point to identify distinct populations within the clinical complexity of the autistic spectrum. In this study, we tried to assess whether distinct subgroups, having distinctive clinical hallmarks, emerge from this comorbid condition.

Methods: Two-hundred and six individuals with idiopathic Autism Spectrum Disorders were subgrouped into three experimental classes depending on the presence of seizures and EEG abnormalities. Neurobehavioral, electroclinical and auxological parameters were investigated to identify differences among groups and features which increase the risk of seizures. Our statistical analyses used ANOVA, post-hoc multiple comparisons, and the Chi-squared test to analyze continuous and categorical variables. A correspondence analysis was also used to decompose significant Chi-squared and reduce variables dimensions.

Results: The high percentage of children with seizures (28.2% of our whole cohort) and EEG abnormalities (64.1%) confirmed that the prevalence of epilepsy in Autism Spectrum Disorders exceeds that of the general population. Seizures were associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature (without macrocephaly) was significantly associated with EEG abnormalities or later onset seizures. However, isolated macrocephaly was equally distributed among groups or associated with early onset seizures when accompanied by tall stature.

Conclusions: Tall stature seems to be a phenotypic "biomarker" of susceptibility to EEG abnormalities or late epilepsy in Autism Spectrum Disorders and, when concurring with macrocephaly, predisposes to early onset seizures. Growth pattern might act as an endophenotypic marker in Autism-Epilepsy comorbidity, delineating distinct pathophysiological subtypes and addressing personalized diagnostic work-up and therapeutic approaches.

Figure 1. Biplot for cross-tabulation of Level of Cognitive Development by Experimental Groups.

Correspondence analysis at two-dimensional solution showed that the ASD-seizures group is relatively associated with severe cognitive delay (closed circle).

Figure 2. Distribution of Z-scores for height (Zh).

A. The histogram of Zh of whole sample shows a significant rightward shift (dashed curve) compared to the normative distribution (closed curve). B. The Zh distribution of ASD “simplex” group shows no difference with respect to normative distribution. C. The Zh distribution of ASD-EEG group shows a significant rightward shift (dashed curve) compared to the normative distribution (closed curve). D. The Zh distribution of ASD-seizures group shows a trend towards a rightward shift (dashed curve) compared to the normative distribution (closed curve). Arrows in C and D indicate a clearly higher rate of tall individuals over 1.5 SDS.

Figure 3. Biplot for Cross-Tabulation of Auxological Categories by Experimental Groups.

Correspondence analysis at two-dimensional solution showed that ASD-EEG group is relatively associated with Isolated Tall Stature (AUX4, closed circle), and ASD-seizures group is relatively associated with combined macrocephaly and tall stature (AUX3, dashed circle).