Risk pathways to autism in a cohort of children and adolescents with Tuberous Sclerosis Complex

Background: Tuberous Sclerosis Complex (TSC) is a single gene disorder carrying high risk of autism spectrum disorder (ASD). Various neurological complications increase the risk of ASD but the way risk factors operate together is unclear. We aimed to explore risk pathways to ASD by modelling the interplay between genetic mutation (TSC1/TSC2), cortical tuber count, seizure type and severity. Methods: The Tuberous Sclerosis 2000 Study is a UK longitudinal study of the natural history of TSC. We recruited newly diagnosed children (N=125) and collected data on mutation, cortical tuber count (cranial MRI/CT), seizure history, and IQ. ASD and IQ assessments were carried out at 10-year follow up (N=86, M age=13.1 years). Structural equation modelling (SEM) was used to explore pathways that mediate between mutation and ASD symptoms. Results: Risk of ASD was high: 39.5% met research criteria for ASD and a further 41.9% showed autistic traits. SEM resulted in two indirect pathways, with cortical tuber count and occurrence/severity of epileptic spasms in infancy mediating between mutation and ASD (mutation-tubers-spasms-ASD, B=2.08, 95%CI 0.15–8.02; mutation-spasms-ASD, B=2.98, 95%CI 0.04–8.89). Concurrent seizures (B=3.08, 95%CI 0.42–6.18) and IQ (B=-117.10, 95%CI -183.57–-59.16) were also associated with ASD symptoms. Conclusions: There was significantly elevated risk of ASD and subclinical autistic traits. Tuber count and severity of spasms predicted ASD severity, suggesting that prevention/control of seizures in infancy may decrease severity of ASD symptoms. ASD was occasionally reported in the absence of overt seizures in infancy, so their causal role requires further investigation

Epilepsy severity mediates association between mutation type and ADHD symptoms in tuberous sclerosis complex.

Funder: Autism Speaks; Id: http://dx.doi.org/10.13039/100000073Funder: Baily Thomas Charitable Fund; Id: http://dx.doi.org/10.13039/501100001262Funder: NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College LondonFunder: Tuberous Sclerosis Association; Id: http://dx.doi.org/10.13039/501100000311The association between attention-deficit/hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load, and mutation were obtained with 125 children ages 0-16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modeling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when intelligence quotient (IQ) was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first 2 years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioral sequelae associated with ADHD from early in life, to further the understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations