We would like to acknowledge and thank the health professional team who undertook this valuable study. The study was done as part of a PhD which was very generously supported by the Romios family’s extraordinary fundraising efforts. We are extremely grateful for their support and hope this study will advance the developmental care of children with TSC.
Aims of the study
The aim of this study was to summarise the results of all available research addressing the factors associated with the development of autism spectrum disorder (ASD) in children with TSC. The main factors investigated were: (1) the potential effects of seizures, (2) the underlying brain abnormalities, especially tubers and (3) genetic factors.
Of 800 potential studies identified, there were 42 suitable studies which included data for 3,542 children with TSC.
What is a systematic review and meta-analysis?
A systematic review is a methodical process that involves searching multiple scientific databases for all the published studies that address the scientific questions being posed. Once all possible studies are identified, two expert clinicians read through them and extract data in a way that allows the combined results to be analysed. The process of combining data from individual studies and undertaking statistical analysis is called ‘meta-analysis ‘. This is a powerful way of combining the results of numerous smaller studies to understand complicated problems. Following meta-analysis, the ‘strength’ of the scientific evidence supporting a finding can be appreciated.
Why investigate ASD in TSC?
ASD is a neurodevelopmental disorder characterised by difficulties with social communication and behaviour that presents on a spectrum from people who are mildly affected through to people who need support in most aspects of daily living. ASD can occur with other problems like intellectual disability, attention deficit hyperactivity disorder and anxiety. Different therapies including speech pathology, psychology, occupational therapy and specialised behavioural programs can be delivered to young children with ASD as ‘early intervention’, to help improve developmental outcomes.
ASD occurs in TSC much more frequently than in the general population. Up to 40-50% of people with TSC have ASD. Understanding the factors that may determine ASD risk allows professionals caring for children with TSC to be on the look-out for early signs of difficulty. Additionally, such understanding helps guide researchers to look for treatments that may improve outcomes.
What did the review find?
It is important to remember that a systematic review and meta-analysis looks at associations not causation. Factors that are associated frequently occur together, but it does not mean that one factor causes the other.
The study identified the following associations between TSC and an increased likelihood of ASD:
- Strong evidence for seizures, especially early onset seizures (before 1 year of age) and infantile spasms.
- Weak evidence for male sex. This result is similar to ASD in people without TSC, where slightly more males than females are affected when intellectual level is considered.
- No evidence for the TSC2 genetic variant being more commonly associated than the TSC1 variant, but the studies were not of sufficiently high quality and more research is needed.
- No evidence for the number, size or distribution of tubers in the brains of people with TSC.
- While there was not sufficient data for statistical analysis, intellectual disability was more common in children with TSC and ASD.
What are the implications of these findings?
Children with TSC and seizures are more likely to develop ASD compared to children with TSC and no seizures, especially if the seizures begin before 1 year of age or are ‘infantile spasms’. Children with TSC and seizures should be carefully monitored for emerging signs of ASD and referred for early intervention services as needed.
More research is needed to understand if seizures are the cause of ASD in TSC or if other TSC factors that are also linked with early seizures are responsible. The increased occurrence of ASD in children with TSC and no seizures compared to the general population suggests that other factors that are part of TSC disease are contributing to the ASD outcome.
Future clinical studies that consider multiple factors side by side, to try and unpack the contributions of each factor are needed to help with our understanding of this.
Mitchell RA, Barton SM, Harvey AS, Ure AM, Williams K. Factors associated with autism spectrum disorder in children with tuberous sclerosis complex: a systematic review and meta-analysis. Dev Med Child Neurol. 2021 Jan 11. doi: 10.1111/dmcn.14787. Online ahead of print. PMID: 33432576 Review.
Full paper available (at extra cost) at: https://pubmed.ncbi.nlm.nih.gov/33432576/
This information is intended to provide some insights into recent TSC-related research. It is not intended to, and it should not, constitute medical or other advice. Readers are warned not to take any action without first seeking medical advice.