Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a Longitudinal, Prospective, Multisite Study

Abstract

Objective: Tuberous sclerosis complex (TSC) is highly associated with autism spectrum disorder (ASD). Objectives of the study were to characterize autistic features in young children with TSC. Methods: Participants included 138 children followed from ages 3 to 36 months with TSC from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study aimed at understanding the underlying mechanisms of ASD in TSC. Developmental and autism-specific assessments were administered, and a clinical diagnosis of ASD was determined for all participants at 36 months. Further analyses were performed on 117 participants with valid autism assessments based on nonverbal mental age greater than 15 months. Results: Prevalence of clinical diagnosis of ASD at 36 months was 25%. Nearly all autistic behaviors on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) were more prevalent in children diagnosed with ASD; however, autism-specific behaviors were also observed in children without ASD. Overall quality of social overtures, facial expressions, and abnormal repetitive interests and behaviors were characteristics most likely to distinguish children with ASD from those without an ASD diagnosis. Participants meeting ADOS-2 criteria but not a clinical ASD diagnosis exhibited intermediate developmental and ADOS-2 scores compared to individuals with and without ASD. Interpretation: ASD is highly prevalent in TSC, and many additional individuals with TSC exhibit a broad range of subthreshold autistic behaviors. Our findings reveal a broader autism phenotype that can be identified in young children with TSC, which provides opportunity for early targeted treatments.

Profiles of autism characteristics in thirteen genetic syndromes: a machine learning approach

“…Future research may consider developing observational measures, which rely less on linguistic ability to assess the diagnostic utility of social-communicative characteristics. Observational measures of autistic characteristics, for instance, have shown to capture variability in phenotypic expression of autistic characteristics in genetic syndromes better than parent-report measures [44,45].…”

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex

“…Tuberous-sclerosis-associated neuropsychiatric disorders (TANDs) include autism spectrum disorder (ASD) (present in 40–50% of individuals), attention deficit hyperactivity disorder (ADHD) (30–50%), and psychomotor delay/intellectual disability (ID) (seen in over 40–50% of individuals) [ 5 , 6 , 7 , 8 ]. Previously, an age-dependent association between epilepsy and ID in individuals with TSC was shown; more specifically, the frequency and the severity of ID increases when epilepsy occurs early in infancy [ 9 ].…”

“…Furthermore, early onset of seizures (before ages 2–5 years old) was shown to be significantly associated with the risk of developing ASD (81%) [ 9 ]. Overall, individuals with TSC and ASD account for 1–4% of all ASD cases [ 5 , 10 , 11 ]. The variable risk of developing ASD or ID is possibly affected by alterations in synaptogenesis and synaptic pruning, connectivity, and long-term potentiation in the mTOR pathway [ 12 , 13 ].…”

Describing autism spectrum disorder in tuberous sclerosis complex: Challenges and future opportunities

“…4 The TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study evaluating early phenotypic features and potential biomarkers of ASD in infants and young children with ASD reported the rate of developmental delay at 45% in all participants with TSC. 3 Differences in rates of developmental delay/ intellectual disability in TSC are likely due to multiple factors, including high rates of comorbid epilepsy with early onset of seizures being associated with an increased risk of developmental delay and autism-related behaviors. 2,5 Although ASD in the setting of TSC/ASD has reportedly similar characteristics compared to non-TSC/ASD, current diagnostic assessments may miss more qualitative differences.…”

“…Tuberous sclerosis complex (TSC) is highly associated with a range of developmental and behavioral challenges, termed TSC‐associated neuropsychiatric disorders (TAND). TSC is one of the most common identifiable genetic causes of autism spectrum disorder (ASD) and is reported to occur in approximately 30%, with a range from 6% to 69% 1–3 . Mitchell et al describe phenotypic characteristics of ASD and associated conditions in children with TSC compared to TSC without ASD and ASD without TSC through a systematic review and meta‐analysis.…”