Abstract
Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6–24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development—BSID, and Autism Diagnostic Observation Schedule—ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy—Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6–12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies.
Highlights
Tuberous Sclerosis Complex (TSC) is a genetic multisystem disorder that is characterized by the formation of hamartomas in several organs and systems [1]
We prospectively evaluated 82 infants with TSC (6–24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development—BSID, and Autism Diagnostic Observation Schedule—Autistic Diagnostic Observation Schedule (ADOS)), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy—Tuberous SclerOsis ComPlex) project (NCT02098759)
These two proteins, along with TBC1D7, form a heterotrimeric complex regulating the activity of mTOR complex 1, which is a key regulator of cell metabolism and proliferation [5]. mTORC1 dysregulation is the main reason for aberrant growth and differentiation underlying the formation of TSC-related lesions, either in the brain and other organs
Summary
Tuberous Sclerosis Complex (TSC) is a genetic multisystem disorder that is characterized by the formation of hamartomas in several organs and systems [1]. It is a rare disease, with an estimated birth incidence of 1 in 5800 [2]. TSC is caused by a mutation in one of the two genes TSC1 or TSC2, which are located on chromosome 9q34 and 16p13.3 respectively, and encoding for hamartin and tuberin [3,4] These two proteins, along with TBC1D7, form a heterotrimeric complex regulating the activity of mTOR complex 1 (mTORC1), which is a key regulator of cell metabolism and proliferation [5]. Early epilepsy onset seems to be the most important factor that influences neurocognitive outcome [8,9], its role can not be considered to be causative [10]
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