Aim To investigate associations between clinical factors and the development of autism spectrum disorder (ASD) in children with tuberous sclerosis complex (TSC), specifically seizures, electroencephalogram abnormalities, tubers and other neurostructural abnormalities, and genetic factors. Method MEDLINE, Embase, PubMed, the Cochrane Library, and Web of Science were searched until January 2019. Studies that considered the predefined factors for development of ASD in children with TSC were included, following PRISMA‐P guidelines. Two authors independently reviewed titles, abstracts, and full texts, extracted data, and assessed risk of bias. Results Forty‐two studies with 3542 children with TSC were included. ASD was associated with a history of seizures (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.77–8.14), infantile spasms compared with other seizure types (OR 3.04, 95% CI 2.17–4.27), onset of any seizure type during infancy (OR 2.65, 95% CI 1.08–6.54), and male sex (OR 1.62, 95% CI 1.23–2.14). There was no association with tuber number, tuber location, or genotype. Interpretation While a causal link between seizures and ASD in children with TSC cannot be inferred, a strong association between seizures and ASD in children with TSC, particularly with seizure onset during infancy and specifically infantile spasms, is present. Children with TSC and infant‐onset seizures should be monitored for emerging features of ASD. Seizures and autism spectrum disorder (ASD) strongly associate in children with tuberous sclerosis complex (TSC). Infant‐onset seizures and infantile spasms are particularly strongly associated with ASD in TSC.
BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant condition, caused by mutations in either the TSC1 or TSC2 gene. It has widespread systemic manifestations and is associated with significant neurological morbidity. In addition to seizures and cerebral pathology including cortical tubers, subependymal nodules, subependymal giant cell astrocytoma and abnormal white matter, there are recognised neuropsychiatric difficulties including intellectual disability, autism spectrum disorder (ASD) and a range of learning and behaviour problems, recently conceptualised as “tuberous sclerosis-associated neuropsychiatric disorders”, or “TAND”. ASD in TSC is of particular importance because (1) it affects up to 50% of people with TSC and is a source of considerable difficulty for them and their families and (2) it provides a model for considering neurobiological pathways involved in ASD. Multiple factors are implicated in the development of ASD in TSC, including (1) seizures and related electrophysiological factors, (2) cerebral pathology, (3) genotype and (4) child characteristics. However, the neurobiological pathway remains unclear. We will conduct a systematic review to investigate and synthesise existing evidence about the role of these risk factors, individually and in combination, in leading to the development of ASD.MethodsOur review will report on all studies that include one or more of four predefined risk factors in the development of ASD in children with TSC. We will search five databases: MEDLINE, EMBASE, PubMed, The Cochrane Library and Web of Science (Conference Proceedings Citation Index). Studies will be selected for reporting after two authors independently (1) review all titles and abstracts, (2) read full text of all appropriate papers and (3) assess for bias using the Newcastle-Ottawa Scale recommended by the Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE guidelines) and the ROBINS-I.DiscussionTo our knowledge, this is the first systematic review investigating multiple risk factors in the development of ASD in children with TSC. Clarifying the evidence in this area will be important to researchers in the field and to clinicians providing prognostic information to families.Systematic review registrationPROSPERO CRD42016042841 Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-017-0448-0) contains supplementary material, which is available to authorized users.
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that can affect most body systems. It is caused by a pathogenic variation in the TSC1 or TSC2 gene, 1,2 which is responsible for producing the proteins hamartin and tuberin respectively. The proteins form a complex involved in inhibiting the mammalian target of rapamycin pathway, which regulates cellular function, including proliferation, growth, and apoptosis. 3 In TSC, neurological characteristics, including seizures and structural brain changes, are common, occurring in around 90% of affected individuals. 4 Autism spectrum disorder (ASD) and intellectual disability are frequent outcomes occurring in around 50%. 5,6 ASD, which occurs in 1% to 4% of the general population, 7,8 is a lifelong neurodevelopmental disorder with social communication and restrictive and repetitive behaviour (RRB) impairments, with severity ranging from mild to profound. Most ASD is considered to be idiopathic, that is, there is no specific, identifiable, underlying cause; however, twin studies suggest that around 80% to 90% of ASD is due to complex, multifactorial
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